[go: up one dir, main page]

CN113316587B - 一种双特异性分子及其制备与用途 - Google Patents

一种双特异性分子及其制备与用途 Download PDF

Info

Publication number
CN113316587B
CN113316587B CN202080009752.8A CN202080009752A CN113316587B CN 113316587 B CN113316587 B CN 113316587B CN 202080009752 A CN202080009752 A CN 202080009752A CN 113316587 B CN113316587 B CN 113316587B
Authority
CN
China
Prior art keywords
ser
val
gly
leu
thr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202080009752.8A
Other languages
English (en)
Other versions
CN113316587A (zh
Inventor
王峰
郑花鸯
张雨菡
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nantong Yichen Biomedical Technology Co ltd
Original Assignee
Nantong Yichen Biomedical Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nantong Yichen Biomedical Technology Co ltd filed Critical Nantong Yichen Biomedical Technology Co ltd
Publication of CN113316587A publication Critical patent/CN113316587A/zh
Application granted granted Critical
Publication of CN113316587B publication Critical patent/CN113316587B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6845—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/642—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C07K16/245—IL-1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Transplantation (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

提供一种双特异性分子及其制备和用途，双特异性分子包括特异性结合白介素1受体(I‑1R)的分子和靶向游离炎症因子的抗体；通过特异性结合细胞表面白介素1受体(L‑1IR)的分子将与之连接的靶向游离炎症因子的抗体聚集在细胞表面或其附近，使得细胞表面或其附近的双特异性分子浓度局部增高，避免了不良反应，提高治疗有效性的同时，降低了患者感染的风险。

Description

一种双特异性分子及其制备与用途
技术领域
本发明属于生物制药领域，具体涉及一种特异性结合白介素1受体(IL-1R)和游离炎症因子的双特异性分子及其制备和用途。
背景技术
促炎症细胞因子调节着机体的各种生理过程，其不正常的上调是各种炎症性疾病发生的主要原因。利用重组抗炎症细胞因子、重组可溶性受体或靶向炎症细胞因子的中和性抗体治疗炎症性疾病已经在临床上取得了较好的效果。
TNF-α是机体在遭受创伤或细菌感染早期产生的促炎症细胞因子。TNFR信号通路传导与多种炎症性疾病如RA(类风湿性关节炎)、克罗恩病(Crohn’s disease)、动脉粥样硬化、银屑病、败血症、糖尿病、肥胖等密切相关。Etanercept(依那西普)是第一个被批准用于治疗类风湿性关节炎的TNF-α抑制剂。靶向TNF-α的Infliximab(英夫利西单抗)也于1998年被FDA批准用于治疗克罗恩病。Infliximab结合单体(非活化状态)或三聚(活化状态)的TNF-α，而Etanercept主要结合活化的TNF-α三聚体。全人源的Adalimumab(阿达木单抗)于2002年被FDA批准用于治疗类风湿性关节炎。TNF-α是对抗细胞内细菌感染的主要因子，因此上述这些TNF-α抑制剂在表现出较好的临床效果的同时，也不可避免地增加了各种感染如肺结核、HBV的重新激活、带状疱疹病毒(herpes zoster virus，HZV)等的风险。作为免疫抑制药物，TNF-α抑制剂在表现出较好临床效果的同时，也大大增加了患者恶性血液肿瘤发生的概率。
与TNF-α家族类似，IL-1家族促炎症信号和抑制炎症信号之间的失衡也与各种慢性疾病的发生密切相关，如炎症性肠病、类风湿性关节炎、与IL-1β过表达有关的自身炎症性疾病等。目前已经有3个靶向IL-1通路的药物(Anakinra(阿那白滞素)，Canakinumab(康纳单抗))和Rilonacept(利纳西普)被FDA批准上市。与Anakinra类似，Canakinumab和Rilonacept可有效减少炎症性疾病的症状，此外，Canakinumab在治疗SJIA(全身型幼年特发性关节炎)方面还表现出较好的疗效。对4个治疗RA的临床试验的荟萃分析发现，坏疽的发生率大大增加。因此，上述这些针对IL-1通路的药物均不推荐用于具有高感染风接受Anakinra治疗的患者肺炎、骨髓炎、蜂窝织炎、滑囊炎、带状疱疹、拇趾囊肿、险的患者。
IL-6是免疫系统中另一个多能干促炎症因子，其由多种细胞分泌，并可刺激B细胞、NK细胞、破骨细胞、肿瘤细胞，因此在自身免疫性疾病如类风湿性关节炎种发挥重要作用。靶向IL-6的人源化抗体Tocilizumab(托珠单抗)分别于2010年和2011年被批准用于RA和SJIA的治疗。靶向IL-6R的Siltuximab(司妥昔单抗)抗体被FDA批准用于免疫缺陷病毒(HIV)阴性且疱疹病毒(HHV-8)阴性的多中心性Castleman病(卡斯特莱曼病)。但是，这两个靶向药物的临床应用也带了诸如TNF-α、IL-1靶向药物类似的不良反应，大大增加了患者感染的几率。靶向效应Th17细胞因子的抗体Ustekinumab(优特克单抗)、Secukinumab(苏金单抗)和ixekizumab(艾塞吉珠单抗)在治疗前被要求接受预防治疗，以避免肺结核重新激活的风险(Rider P,Carmi Y and Cohen I.Int J Cell Biol.2016:9259646)。
开发同时靶向上述通路的双特异性抗体，各大制药公司已经进行了多种尝试，例如靶向TNF-α和IL-17A的多个双特异性抗体如ABT-12、COVA-322、LY3114062、BCD-121等在临床试验过程中发现疗效未达预期(Baker,KF.et al.Ann Rheum Dis.2018,77(2):175-187)。Abbott公司靶向IL-1α和IL-1β的双抗ABT-981最近的II期临床结果显示，ABT-981对侵蚀性手骨关节炎(HOA)的疼痛或影像学终点无改善作用，对Western Ontario和McMasterUniversities Osteoarthritis(WOMAC)疼痛改善有限，未见对滑膜炎的改善作用(Kloppengurg,M.et al.Ann Rheum Dis.2019,78:413-420和Fleischmann,RM.etal.Arthritis Rheumatol.2019,doi:10.1002/art.40840)。
因此，本领域急需一种双特异性抗体，在提高其临床治疗炎症性疾病效果的同时，大大减少其对机体带来的不良反应。
本发明简述
本发明提供了一种双特异性分子及其制备与用途。
目前针对促炎症因子的药物多数针对的是体内游离的炎症因子，这些药物与炎症因子结合后随体液在全身循环，因此可能会带来对机体的全身不良反应，增加机体感染的风险。本发明人发现，通过特异性结合细胞表面炎症因子受体的分子为媒介，将靶向游离炎症因子的抗体局限在细胞表面或其附近，可以发挥两者协同的、局部的抗炎症效应，在增强抗炎症效应的同时，可有效避免双特异性分子在全身循环可能带来的不良反应。
基于上述发现，本发明提供了一种双特异性分子，所述双特异性分子包括特异性结合IL-1R的分子和靶向游离炎症因子的抗体，其中，所述特异性结合IL-1R的分子与所述靶向炎症因子的抗体通过连接肽连接。本发明所述的双特异性分子，通过特异性结合IL-1R的分子，将双特异性分子聚集到表达IL-1R的细胞表面或其附近，避免其在体内随体液进行全身循环；接着，靶向游离炎症因子的抗体可进一步中和表达IL-1R的细胞表面或其附近由于炎症局部增高的游离炎症因子，在协同增强特异性结合IL-1R的分子的抗炎症反应的同时，避免了因游离炎症因子在体内广泛表达而导致靶向游离炎症因子的抗体产生对机体的不良反应。
在某些实施方式中，特异性结合IL-1R的分子为非免疫球蛋白多肽。在某些实施方式中，所述特异性结合IL-1R的非免疫球蛋白多肽为IL-1RA。在某些实施方式中，所述特异性结合IL-1R的IL-1RA具有如SEQ ID NO:49所示核苷酸序列和或具有如SEQ ID NO:50所示的氨基酸序列。在某些实施方式中，所述特异性结合IL-1R的非免疫球蛋白多肽为具有与SEQ ID NO:50具有至少85％-99％同源性的氨基酸序列组成。
在某些实施方式中，特异性结合IL-1R的分子为抗IL-1R抗体。在某些实施方式中，特异性结合IL-1R的抗体为单域抗体、嵌合抗体、人源化抗体、人源抗体或上述这些抗体的重组改变部分。在某些实施方式中，所述特异性结合IL-1R的抗体包括CDR组：HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3，其中，HCDR1、HCDR2和HCDR3具有如SEQ ID NO:52、SEQ ID NO:56或SEQ ID NO:58所示的氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列；LCDR1、LCDR2和LCDR3具有如SEQ ID NO:54或SEQ ID NO:60所示的氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列。在某些实施方式中，特异性结合L-1R的抗体由如下重链和轻链组成：SEQ IDNO:52所示的重链和SEQ ID NO:54所示的轻链；SEQ ID NO:56所示的重链和SEQ ID NO:54所示的轻链；或者，SEQ ID NO:58所示的重链和SEQ ID NO:60所示的轻链。
在某些实施方式中，所述双特异性分子靶向的游离炎症因子选自以下(不限于)其中之一：IL-1超家族(IL-1α、IL-1β、IL-18、IL-33、IL-36α、IL-36β、IL-36γ)、IL-4、IL-13、IL-17A、IL-17E、IL-6、IL-12、IL-23、TNF超家族(TNFα、TNFβ、TNFγ、OX40L(TNFSF4)、CD40L(CD154)、FasL(CD178、CD95L)、CD27L(CD70)、CD30L(CD153)、4-1BBL、CD253(APO-2L)、CD254、APO-3L(DR3L)、CD256(TALL-2)、CD257(BlyS)、LIGHT(CD258)、TL1(TNFSF18、AITRL)、ED1-A1、BAFF、IFN或GM-CSF。
在某些实施方式中，靶向前述游离炎症因子的抗体为嵌合抗体、人源化抗体、人源抗体或上述这些抗体的重组改变部分。
在某些具体的实施方式中，所述双特异性分子靶向的游离炎症因子为IL-1β。在某些实施方式中，所述靶向游离炎症因子IL-1β的抗体具有如SEQ ID NO:2所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列，以及如SEQ ID NO:4所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列；或者具有如SEQ ID NO:6所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列，以及如SEQ ID NO:8所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列。
在某些具体些实施方式中，所述双特异性分子靶向的游离炎症因子为IL-17A。在某些实施方式中，所述靶向游离炎症因子IL-17具有如SEQ ID NO:26所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列，以及如SEQ ID NO:28所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列。
在某些具体实施方式中，所述双特异性分子靶向的游离炎症因子为IL-6。在某些实施方式中，所述靶向游离炎症因子IL-6的抗体具有如SEQ ID NO:38所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列，以及如SEQ ID NO:40所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列。
在某些实施方式中，本发明的双特异性分子包括特异性结合IL-1R的分子和靶向游离炎症因子IL-1β的抗体，所述特异性结合IL-1R的分子与所述靶向游离炎症因子IL-1β的抗体通过连接肽连接。在某些实施方式中，所述靶向游离炎症因子IL-1β的人源化抗体具有SEQ ID NO:2所示的重链和SEQ ID NO:4所示的轻链。在某些实施方式中，所述靶向游离炎症因子IL-1β的人源化抗体具有如SEQ ID NO:6所示的重链和SEQ ID NO:8所示的轻链。在某些实施方式中，所述特异性结合IL-1R的分子为非免疫球蛋白多肽。在某些实施方式中，特异性结合IL-1R的分子的非免疫球蛋白多肽为IL-1RA。在某些实施方式中，特异性结合IL-1R的非免疫球蛋白多肽具有如SEQ ID NO:49所示的核苷酸序列和/或具有如SEQ IDNO:50所示的氨基酸序列。在某些实施方式中，所述特异性结合IL-1R的非免疫球蛋白多肽为具有与SEQ ID NO:50具有至少85％-99％同源性的氨基酸序列组成。在某些实施方式中，所述特异性结合IL-1R的分子为抗IL-1R的抗体。在某些实施方式中，所述特异性结合IL-1R的抗体具有包括CDR组：HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3，其中，HCDR1、HCDR2和HCDR3具有如SEQ ID NO:52、SEQ ID NO:56或SEQ ID NO:58所示的氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列；LCDR1、LCDR2和LCDR3具有如SEQ ID NO:54或SEQ ID NO:60所示的氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列。在某些实施方式中，所述特异性结合IL-1R和IL-1β的双特异性分子具有如下氨基酸序列的重链和轻链：SEQ ID NO:10和SEQ IDNO:4；SEQ ID NO:2和SEQ ID NO:12；SEQ ID NO:14和SEQ ID NO:4；SEQ ID NO:2和SEQ IDNO:16；SEQ ID NO:18和SEQ ID NO:4；SEQ IDNO:2和SEQ ID NO:20；SEQ ID NO:6和SEQ IDNO:22；SEQ ID NO:6和SEQ ID NO:24；SEQ ID NO:62和SEQ ID NO:4；SEQ ID NO:64和SEQID NO:4；SEQ ID NO:66和SEQ ID NO:8；SEQ ID NO:6和SEQ ID NO:68；SEQ ID NO:70和SEQID NO:4；SEQ ID NO:72和SEQ ID NO:4；SEQ ID NO:74和SEQ ID NO:4；SEQ ID NO:76和SEQID NO:4。
在某些实施方式中，本发明的双特异性分子包括特异性结合IL-1R的分子和靶向游离炎症因子IL-17的抗体，所述特异性结合IL-1R的分子与所述靶向游离炎症因子IL-17的抗体通过连接肽连接。在某些实施方式中，所述靶向游离炎症因子IL-17的人源化抗体具有SEQ ID NO:26所示的重链和SEQ ID NO:28所示的轻链。在某些实施方式中，所述特异性结合IL-1R的分子为非免疫球蛋白多肽。在某些实施方式中，特异性结合IL-1R的分子的非免疫球蛋白多肽为IL-1RA。在某些实施方式中，特异性结合IL-1R的非免疫球蛋白多肽IL-1RA具有如SEQ ID NO:49所示的核苷酸序列和/或具有如SEQ ID NO:50所示的氨基酸序列。在某些实施方式中，所述特异性结合IL-1R的非免疫球蛋白多肽为具有与SEQ ID NO:50具有至少85％-99％同源性的氨基酸序列组成。在某些实施方式中，所述特异性结合IL-1R的分子为抗IL-1R的抗体。在某些实施方式中，所述特异性结合IL-1R的抗体具有包括CDR组：HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3，其中，HCDR1、HCDR2和HCDR3具有如SEQ ID NO:52、SEQ ID NO:56或SEQ ID NO:58所示的氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列；LCDR1、LCDR2和LCDR3具有如SEQ ID NO:54或SEQ ID NO:60所示的氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列。在某些实施方式中，所述特异性结合IL-1R和IL-17的双特异性分子具有如下氨基酸序列的重链和轻链：SEQ ID NO:34和SEQ ID NO:28；SEQ ID NO:26和SEQ ID NO:36；SEQ ID NO:30和SEQ ID NO:28；SEQ ID NO:26和SEQ ID NO:32。
在某些实施方式中，本发明的双特异性分子包括特异性结合IL-1R的分子和靶向游离炎症因子IL-6的抗体，所述特异性结合IL-1R的分子与所述靶向游离炎症因子IL-6的抗体通过连接肽连接。在某些实施方式中，所述靶向游离炎症因子IL-6的人源化抗体具有SEQ ID NO:38所示的重链和SEQ ID NO:40所示的轻链。在某些实施方式中，所述特异性结合IL-1R的分子为非免疫球蛋白多肽。在某些实施方式中，特异性结合IL-1R的分子的非免疫球蛋白多肽为IL-1RA。在某些实施方式中，特异性结合IL-1R的非免疫球蛋白多肽IL-1RA具有如SEQ ID NO:49所示的核苷酸序列和/或具有如SEQ ID NO:50所示的氨基酸序列。在某些实施方式中，所述特异性结合IL-1R的非免疫球蛋白多肽为具有与SEQ ID NO:50具有至少85％-99％同源性的氨基酸序列组成。在某些实施方式中，所述特异性结合IL-1R的分子为抗IL-1R的抗体。在某些实施方式中，所述特异性结合IL-1R的抗体具有包括CDR组：HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3，其中，HCDR1、HCDR2和HCDR3具有如SEQ ID NO:52、SEQ ID NO:56或SEQ ID NO:58所示的氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列；LCDR1、LCDR2和LCDR3具有如SEQ ID NO:54或SEQ ID NO:60所示的氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列。在某些实施方式中，所述特异性结合IL-1R和IL-6的双特异性分子具有如下氨基酸序列的重链和轻链：SEQ ID NO:46和SEQ ID NO:40；SEQ IDNO:38和SEQID NO:48；SEQ ID NO:38和SEQ ID NO:44；SEQ ID NO:42和SEQ ID NO:40。
一方面，本发明提供了编码上述双特异性分子的多核苷酸。
在某些实施方式中，编码特异性结合IL-1R和靶向游离炎症因子IL-1β的双特异性分子具有如下核苷酸序列的重链和轻链：SEQ ID NO:9和SEQ ID NO:3；SEQ ID NO:1和SEQID NO:11；SEQ ID NO:13和SEQ ID NO:3；SEQ ID NO:1和SEQ ID NO:15；SEQ ID NO:17和SEQ ID NO:3；SEQ ID NO:1和SEQ ID NO:19；SEQ ID NO:5和SEQ ID NO:21；SEQ ID NO:5和SEQ ID NO:23；SEQ ID NO:61和SEQ ID NO:3；SEQ ID NO:63和SEQ ID NO:3；SEQ ID NO:65和SEQ ID NO:7；SEQ ID NO:5和SEQ ID NO:67；SEQ ID NO:69和SEQ ID NO:3；SEQ ID NO:71和SEQ ID NO:3；SEQ ID NO:73和SEQ ID NO:3；SEQ ID NO:75和SEQ ID NO:3。。
在某些实施方式中，编码特异性结合IL-1R和靶向游离炎症因子IL-17的双特异性分子具有如下核苷酸序列的重链和轻链：SEQ ID NO:33和SEQ ID NO:27；SEQ ID NO:25和SEQ ID NO:35；SEQ ID NO:29和SEQ ID NO:27；SEQ ID NO:25和SEQ ID NO:31。
在某些实施方式中，编码特异性结合IL-1R和靶向游离炎症因子IL-6的双特异性分子具有如下核苷酸序列的重链和轻链：SEQ ID NO:45和SEQ ID NO:39；SEQ ID NO:37和SEQ ID NO:47；SEQ ID NO:37和SEQ ID NO:43；SEQ ID NO:41和SEQ ID NO:39。
一方面，本发明提供了一种表达载体，所述表达载体包含本发明的多核苷酸。一方面，本发明提供了一种宿主细胞，所述宿主细胞包含本发明的表达载体。
一方面，本发明提供了一种药物组合物，其包含本发明的双特异性分子和药学上可接受的载体或制剂。
另一方面，本发明还提供了一种治疗治疗有需要的受试者的炎症性疾病和/或自身免疫性疾病的方法，所述方法包括对所述受试者施用治疗有效量的组合物，所述组合物包含药学可接受形式的本发明所述的双特异性分子。
如上所述，本发明提供了一种双特异性分子及其制备和用途，通过特异性结合IL-1R的分子(如非免疫球蛋白多肽IL-1RA、IL-1R抗体)将与之连接的靶向游离炎症因子(如IL-1β、IL-17或IL-6)的抗体聚集在细胞表面或其附近，使得细胞表面或其附近的双特异性分子浓度局部增高，不仅避免了相关技术中使用靶向一个或多个游离炎症因子的抗体在全身循环带来的不良反应，而且还避免了相关技术中使用靶向单一炎症因子受体所带来的疗效受限问题，在大大提高治疗有效性的同时，极大降低了患者感染的风险。
附图说明
构成本申请的附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定，在附图中：
图1为SDS-PAGE图，其中M为蛋白marker，“-”表示上样时不加还原剂DTT，“+”表示上样时加还原剂DTT。图1A为特异性结合IL-1R和IL-1β的双特异分子SDS-PAGE图，其中泳道1-8分别为：BSI-1、BSI-2、BSI-3、BSI-4、BSI-5、BSI-6、BSI-7、BSI-8；图1B为特异性结合IL-1R和IL-17A的双特异分子SDS-PAGE图，其中泳道1为aIL-17AH，泳道2-5分别为:BSI-9、BSI-12、BSI-11、BSI-10；图1C为特异性结合IL-1R和IL-6的双特异分子SDS-PAGE图，其中泳道1为aIL-6，泳道2-5分别为：BSI-13、BSI-15、BSI-16、BSI-14
图2为凝胶排阻层析分析结果，其中图2A为特异性结合IL-1R和IL-17的双特异分子凝胶排阻层析结果，图2B为靶向IL-1R和IL-6的双特异分子凝胶排阻层析结果
图3为结合IL-1R和IL-1β的双特异性分子与重组人IL-1β、、重组鼠IL-1β、重组人IL-1R、重组鼠IL-1R ELISA检测结果
图4为特异性结合IL-1R和IL-1β的双特异分子抑制IL-1β诱导的HEK-Blue-IL1R细胞信号通路，其中4A为重组人IL-1β诱导HEK-Blue-IL1R细胞信号通路，4B为双特异性分子aIL-1β-1与IL-1RA单用或联合使用对IL-1β诱导的HEK-Blue-IL1R细胞信号通路的抑制，4C-4F为双特异分子(IL-1RA与aIL-1β-1融合)对IL-1β诱导的HEK-Blue-IL1R细胞信号通路的抑制
图5为特异性结合IL-1R和IL-1β的双特异分子在小鼠模型上的有效性研究，其中Blank为未注射任何药物或human IL-1β的实验组；DPBS组为先注射DPBS，24小时后注射human IL-1β；1为aIL-1β-1给药组，2为双特异性分子(IL-1RA与aIL-1β-1融合)给药组，3为isotype对照抗体给药组，4为IL-1RA与isotype抗体融合给药组。其中，“*”：与DPBS组相比p<0.05；“**”：与DPBS组相比p<0.005；“***”：与DPBS组相比p<0.0005。
图6为特异性结合IL-1R和IL-17A的双特异分子与IL-17结合ELISA
图7为特异性结合IL-1R和IL-6的双特异分子与IL-6结合ELISA
图8显示了三个抗-IL-1R抗体重链可变区的氨基酸序列比对。互补决定区(CDRs)为下划线标出的部分。
图9显示了三个抗-IL-1R抗体轻链可变区的氨基酸序列比对。互补决定区(CDRs)为下划线标出的部分。
图10显示了aIL-1β-1抗体重链和轻链可变区，互补决定区(CDRs)为下划线标出的部分。
图11显示了aIL-1β-2抗体重链和轻链可变区，互补决定区(CDRs)为下划线标出的部分。
图12显示了aIL-17A抗体重链和轻链可变区，互补决定区(CDRs)为下划线标出的部分。
图13显示了aIL-16抗体重链和轻链可变区，互补决定区(CDRs)为下划线标出的部分。
本发明的详述
本发明在此通过对使用下述定义和实施例的引用进行详细描述。所有在本文中提及的专利和公开文献的内容，包括在这些专利和公开中披露的所有序列，明确地通过提述并入本文。
双特异性分子
本发明的“双特异性分子”是具有两种结合特异性的结合分子，其可以是具有抗原结合特异性的非免疫球蛋白多肽，也可以是具有抗原结合特异性的抗体。
抗体
本发明的“抗体”指免疫球蛋白分子、免疫球蛋白分子的片段，或其任一者的衍生物，其具有以下的能力：在典型的生理条件下特异性结合抗原，以诱导、促进、提高和/或调节与抗体结合抗原有关的生理反应。除非上下文另外指明或明显矛盾，本发明的“抗体”包括抗体的片段，其为抗原-结合片段，即，保留特异性结合抗原的能力。
结合IL-1R的分子
本发明中所述的“特异性结合IL-1R的分子”是指能与IL-1α和/或IL-1β竞争结合IL-1R，并抑制IL-1R生物活性的非免疫球蛋白多肽或抗体。其它能与IL-1α和/或IL-1β竞争结合IL-1R，并抑制IL-1R生物活性的单域抗体、重链抗体也包括在本发明中。
炎症因子
如本申请所用“炎症因子”是参与炎症发生、发展的细胞因子的总称。“游离的炎症因子”是指在体内以溶液中的形式存在的、不表达于细胞表面的炎症因子，常见的游离炎症因子包括但不限于如下所列例子：IL-1超家族(IL-1α、IL-1β、IL-18、IL-33、IL-36α、IL-36β、IL-36γ)、IL-4、IL-13、IL-17A、IL-17E、IL-6、IL-12、IL-23、TNF超家族(TNFα、TNFβ、TNFγ、OX40L(TNFSF4)、CD40L(CD154)、FasL(CD178、CD95L)、CD27L(CD70)、CD30L(CD153)、4-1BBL、CD253(APO-2L)、CD254、APO-3L(DR3L)、CD256(TALL-2)、CD257(BlyS)、LIGHT(CD258)、TL1(TNFSF18、AITRL)、ED1-A1)、BAFF、IFN或GM-CSF等。炎症因子受体是指可与炎症因子结合、且表达于细胞表面的分子。
CDR
术语“CDR”是指在免疫球蛋白可变区序列内的互补决定区。对于各重和轻链可变区，在重链和轻链的各可变区中存在三个CDR，其被命名为CDR1、CDR2和CDR3。术语“CDR组”是指在能够结合抗原的单一可变区中出现的三个CDR的组。这些CDR的确切边界已根据不同系统不同地定义。由Kabat(Kabat等(1987)和(1991))描述的系统，不仅提供了可适用于抗体或结合蛋白的任何可变区的明确残基编号系统，而且还提供了定义各重链或轻链序列中的三个CDR的精确残基边界。这些CDR可以被称为Kabat CDR。Chothia和同事(Chothia和Lesk(1987)J.Mol.Biol.196:901-917；Chothia等(1989)Nature342:877-883)发现KabatCDR内的某些亚部分采取几乎相同的肽骨架构象，尽管在氨基酸序列水平上具有大的多样性。这些亚部分被命名为L1、L2和L3或H1、H2和H3，其中“L”和“H”分别指轻链和重链区域。这些区域可以被称为ChothiaCDR，所述Chothia CDR具有与Kabat CDR重叠的边界。定义与Kabat CDR重叠的CDR的其它边界已由Padlan(1995)FASEB J.9:133-139和MacCallum(1996)J.Mol.Biol.262(5):732-45)描述。还有其它CDR边界定义可以不严格遵循本文系统之一，但仍将与Kabat CDR重叠，尽管鉴于特定残基或残基组或甚至整个CDR不显著影响抗原结合的预测或实验发现，它们可以缩短或加长。本文使用的方法可以利用根据这些系统中的任一种定义的CDR，尽管某些实施方案使用Kabat或Chothia定义的CDR(CN105324396A)。
术语“同源性”或“同一性”指两个聚合物分子之间(例如，在两个核酸分子(如，两个DNA分子或两个RNA分子之间)或在两个多肽分子之间)的次级单位序列同一性。当这两个分子中的次级单位位置被相同单体性次级单位占据时，例如，若两个DNA分子中每个分子中的某位置被腺嘌呤占据，则它们在该位置是同源或相同的。两个序列之间的同一性直接随匹配位置或同源位置的数目而变化，例如，如果两个序列中一半位置(例如长度为十个次级单位的聚合物中的五个位置)是同源的，则这两个序列是50％同源的(亦可称具有50％同源性或50％同一性)；如果90％的位置(例如10个位置中9个位置)是匹配或同源的，这这两个序列是90％同源的(亦可称具有90％同源性或90％同一性)。
炎症性疾病
如本申请所用的“炎症性疾病”指的是与炎症反应有关的疾病。炎症性疾病的实例包括关节炎如RA、牛皮癣银屑病关节炎、强直性脊柱炎、青少年特发性关节炎以及关节的其他炎症疾病，炎性肠疾病如溃疡性结肠炎、克罗恩氏病、巴雷特综合征(Barrett′ssyndrome),回肠炎、肠炎、谷蛋白敏感性肠病，呼吸系统的炎性病症，诸如哮喘、成人呼吸窘迫综合征、变态反应性鼻炎、矽肺、慢性呼吸道阻塞性疾病、超敏反应肺疾病、支气管扩张症；炎症性皮肤的炎症疾病,包括银屑病、硬皮病和诸如湿疹、特应性皮炎、荨麻疹和瘙痒症的炎症皮肤病；涉及中枢和外周围神经系统炎症的病症包括多发性硬化、特发性脱髓鞘性多神经病、格-巴二氏综合征(Guillain-Barre syndrome)、慢性炎症性脱髓鞘性多发性神经病和诸如阿尔茨海默氏病的神经变性疾病；系统性红斑性狼疮,免疫介导性肾脏病，例如肾小球肾炎和脊椎关节病；带有不良慢性炎症成分的疾病，诸如系统性硬化病,特发性炎症性肌病,肖格伦氏综合征(Sjogren′s syndrome),脉管炎,肉瘤样病,甲状腺炎,痛风,耳炎,结膜炎,窦炎,肉瘤样病,贝赫切特综合征(Behcet′s syndrome),肝胆管疾病诸如肝炎、原发性胆汁性肝硬化、肉芽肿性肝炎和硬化性胆管炎；炎症和心血管系统的缺血损伤诸如缺血性心脏病,中风和动脉粥样硬化；以及移植物排斥(graftrejection),包括同种异体移植排斥和移植物抗宿主病。各种其它炎症疾病包括肺结核和慢性胆囊炎。例如在Harrison′sPrinciples of Internal Medicine(哈里森内科学),12th Edition,Wilson,et al.,eds.,McGrawill,Inc.)中也描述了其它慢性炎症疾病。
药物组合物
通过混合具有想要纯度的本发明双特异性抗体与一种或多种任选的药学上可接受的载体来制备如本文所述的药物组合物，其为冻干制剂或水溶液的形式。药学可接受的载体在采用的剂量和浓度下对接受者一般是无毒的。
本发明可以作为单独的活性成分，或与例如佐剂或与其他药物例如免疫抑制或免疫调节剂或其他抗炎剂组合施用，例如用于治疗炎症性疾病和/或免疫性疾病。
实施例
需要说明的是，在不冲突的情况下，本申请中的实施例仅为举例说明，不旨在对本发明造成任何方式上的限制。
实施例1特异性结合IL-1R和IL-1β的双特异分子的构建、表达、纯化和功能检测
实施例1.1特异性结合IL-1R和IL-1β的双特异分子的克隆
分别合成编码aIL-1R-1、aIL-1R-2、aIL-1R-3、aIL-1β-1、aIL-1β-2抗体的重链(HC)和轻链(LC)、IL-1RA的基因片段，采用标准分子生物学技术通过连接肽将IL-1RA融合在aIL-1β抗体(aIL-1β-1和aIL-1β-2)重链N端、轻链N端、重链C端或轻链C端，将aIL-1R抗体的VH和VL分别通过连接肽融合到aIL-1β抗体重链和轻链的N端，或者将aIL-1β抗体的VH和VL分别通过连接肽融合到aIL-1R抗体重链的N端和轻链的N端，所有的序列都通过测序验证。
表1双特异分子核酸和序列
实施例1.2特异性结合IL-1R和IL-1β的双特异分子的表达和纯化
将实施例1.1构建好的表达载体重链和轻链瞬时转染FreeStyle HEK293细胞(ThermoFisher)，转染时重链的质粒和轻链的质粒用量为摩尔比1:1)：将28ml FreeStyleHEK293(共3×107细胞)接种至125ml细胞培养瓶，质粒用1ml Opti-MEM(Invitrogen)稀释后加至1ml含60μl 293Fectin(Invitrogen)的Opti-MEM中，室温静置30min，将质粒-293Fectin mixture加至细胞培养液中125rpm，37℃，5％CO2培养。分别于转染后48h和96h收集细胞培养上清，Protein A Resin(Thermo Fisher Scientific)纯化。通过SDS-PAGE分析这些蛋白质。结果如图1A所示，说明成功表达出了预期的双特异性分子。
实施例1.3特异性结合IL-1R和IL-1β的双特异分子质谱分析
将实施例2中获得的Protein A resin纯化后的样品与PNGase F(NEB)37℃孵育8小时后，加10mM二硫苏糖醇处理后，将样品注射进HPLC-Q-TOF-MS(Agilent,USA)的300SB-C8,2.1x 50mm柱，进行质谱分析。如表2所示，不同融合形式的抗体融合蛋白利用质谱检测得到的分子量与理论预测值基本一致。
表2双特异分子理论分子量及MS检测分子量
实施例1.4特异性结合IL-1R和IL-1β的双特异分子体外结合分析
包被重组人IL-1β(ThermoFisher Scientific)、重组小鼠IL-1β(SinoBio)、重组小鼠IL-1R(SinoBio)、重组人IL-1R(100ng/孔)(DPBS buffer，pH7.4)于96孔板，4℃孵育过夜；含2％脱脂奶粉的PBST(0.5％Tween-20in PBS)室温封闭1小时，经PBST洗3次后，分别加入梯度稀释的双特异分子(0.006nM-100nM)37℃孵育1h，PBST洗3次后，加入2％milk/PBST稀释的anti-human Fc-HRP(KPL；1:2500)二抗室温孵育1h，PBST洗5次后，QuantaBlu荧光过氧化物酶底物(Life technologies,Cat.15169)显色后于325nm和420nm处读数，或者TMB显色试剂(BioLegend)显色后于650nm处读数。
Prizm Graphpad软件用non-linear regression中specific binding模型对数据进行非线性回归。
结果如图3所示，靶向IL-1R和IL-1β的双特异分子对人IL-1β或鼠IL-1β的结合能力与aIL-1β-2抗体类似，说明IL-1RA的融合对aIL-1β抗体与IL-1β的结合影响很小。双特异分子对人IL-1β的结合能力大约是对小鼠IL-1β结合能力的5-7倍。
实施例1.5重组人IL-1β激活HEK-Blue-IL1R细胞分析
5x104 HEK-Blue-IL1R细胞(InvivoGene)铺于96孔板，每孔加100ul梯度稀释(0.024-50ng/ml)的IL-1β(R&D systems)(用5％FBS/DMEM的培养基稀释)，培养过夜。取细胞上清与QUANTI-Blue(InvivoGene)按1：9混匀，37℃孵育4小时后，Spectramaxfluorescence plate reader读取655nm波长的吸光度。数据用PrizmGraphpad软件“non-linear regression”中的log[agonist]vs response(3parameters)模型绘制和分析。如图4A所示，IL-1β具有较强的刺激HEK-Blue-IL1R细胞通路的能力，其EC50为1.54±0.35ng/ml。图4B-4F显示，aIL-1β抗体(aIL-1β-1或aIL-1β-2)上融合IL-1RA后，其抑制IL-1β诱导的HEK-Blue-IL1R细胞信号通路的能力强于单独的IL-1RA、aIL-1β抗体或IL-1RA+aIL-1β联用，提示双特异分子的IL-1RA与aIL-1β对IL-1R具有协同抑制作用。
实施例1.6特异性结合IL-1R和IL-1β的双特异分子体内有效性研究。
将DPBS或双特异分子(两个剂量：5mg/kg，15mg/kg)腹腔注射雌性C57BL/6小鼠(6-7周)，24小时后，往上述小鼠每只注射20ng重组人IL-1β(PHC0815,ThermoFisherScientific)。2小时后，后眼窝取血，根据厂家提供的说明书，利用Mouse IL-6ELISAMAXTMDeluxe(Cat.431306，BioLegend)检测小鼠血浆中mIL-6的水平。数据用PrizmGraphpad软件绘制和分析。统计分析采用非配对、双尾t检验。
结果如图5所示：与Blank组相比，DPBS组小鼠体内IL-6的水平明显上调。相比于DPBS组，给药组中，15mg/ml和5mg/ml剂量的IL-1RA与aIL-1β-1融合的双特异性分子可以显著抑制IL-1β引起的小鼠IL-6的上调；注射15mg/ml剂量的IL-1RA与isotype的融合抗体只能一定程度上抑制IL-1β引起的小鼠IL-6的上调。
实施例2特异性结合IL-1R和IL-17的双特异分子的构建、表达、纯化和功能检测实施例
2.1特异性结合IL-1R和IL-17的双特异分子的克隆
分别合成编码aIL-17抗体重链和轻链的基因片段，采用标准分子生物学技术通过连接肽L1、L2或L3将IL-1RA融合在aIL-17抗体重链N端、轻链N端、重链C端或轻链C端。
通过连接肽L4和L5将aIL-1R抗体的VH和VL分别融合到aIL-17抗体重链和轻链的N端，或者将aIL-17抗体的VH和VL分别融合到aIL-1R抗体重链的N端和轻链的N端，所有的序列都通过测序验证。
实施例2.2特异性结合IL-1R和IL-17的双特异分子的表达、纯化和分析
将实施例2.1构建好的表达载体重链和轻链瞬时转染FreeStyle HEK293细胞(ThermoFisher)，转染时重链的质粒和轻链的质粒用量为摩尔比1:1：将28ml FreeStyleHEK 293(共3×10 7细胞)接种至125ml细胞培养瓶，质粒用1ml Opti-MEM(Invitrogen)稀释后加至1ml含60μl 293Fectin(Invitrogen)的Opti-MEM中，室温静置30min，将质粒-293Fectin mixture加至细胞培养液中125rpm，37℃，5％CO2培养。分别于转染后48h和96h收集细胞培养上清，Protein A Resin(Thermo Fisher Scientific)纯化。通过SDS-PAGE分析这些蛋白质。结果如图1B所示，各泳道条带的大小与预期的一致，说明成功表达出了预期的双特异性分子。
为进一步研究双特异分子在溶液中的物理特性，用GE的AKTA chromatography进行凝胶排阻层析。所用的层析柱为HiLoad 16/600Superdex 200凝胶排阻层析柱，凝胶排阻层析所用的溶液为DPBS缓冲液(0.010M phosphate buffer,0.0027M KCl,0.14M NaCl,pH7.4)，凝胶排阻层析所用的流速为0.4ml/min。
图2A的凝胶排阻层析结果显示，所获得的双特异分子主要以单体形式存在，并且具有较高的纯度，无明显可见聚集。
实施例2.3特异性结合IL-1R和IL-17的双特异分子体外结合分析
包被重组人IL-17(SinoBiological)(100ng/孔)(PBS buffer，pH7.4)于96孔板，4℃孵育过夜；含2％脱脂奶粉的PBST(0.5％Tween-20in PBS)室温封闭1小时，经PBST洗3次后，分别加入梯度稀释的双特异分子(0.04nM-30nM)37℃孵育1h，PBST洗3次后，加入2％milk/PBST稀释的anti-human Fc-HRP(KPL,1:2500)二抗室温孵育1h，PBST洗5次后TMB(BioLegend)显色，Thermal VARIOSKAN FLASH plate reader在650nm波长下读数，数据用PrizmGraphpad软件“non-linear regression”中的log[agonist]vs response(3parameters)模型绘制和分析。
图6的ELISA结果显示，IL-1RA与aIL-17A抗体重链或轻链的融合并不影响aIL-17A抗体对IL-17的亲和力，靶向IL-1RA和IL-17的双特异分子对IL-17的亲和力与aIL-17A抗体相似。
实施例3特异性结合IL-1R和IL-6的双特异分子的构建、表达、纯化和功能检测
实施例3.1特异性结合IL-1R和IL-6的双特异分子的克隆
分别合成编码aIL-6抗体重链和轻链的基因片段，采用标准分子生物学技术通过连接肽L1、L2或L3将IL-1RA融合在aIL-6抗体重链N端、轻链N端、重链C端或轻链C端，通过连接肽L4和L5将aIL-1R抗体的VH和VL分别融合到aIL-6抗体重链和轻链的N端，或者将aIL-6抗体的VH和VL分别融合到aIL-1R抗体重链的N端和轻链的N端，所有的序列都通过测序验证。
实施例3.2特异性结合IL-1R和IL-6的双特异分子的表达、纯化和分析
将实施例3.1构建好的表达载体重链和轻链瞬时转染FreeStyle HEK293细胞(ThermoFisher)，转染时重链的质粒和轻链的质粒用量为摩尔比1:1：将28ml FreeStyleHEK293(共3×107细胞)接种至125ml细胞培养瓶，质粒用1ml Opti-MEM(Invitrogen)稀释后加至1ml含60μl 293Fectin(Invitrogen)的Opti-MEM中，室温静置30min，将质粒-293Fectin mixture加至细胞培养液中125rpm，37℃，5％CO2培养。分别于转染后48h和96h收集细胞培养上清，Protein A Resin(Thermo Fisher Scientific)纯化。通过SDS-PAGE分析这些蛋白质。结果如图1C所示，各泳道条带的大小与预期的一致，说明成功表达出了预期的双特异性分子。
为进一步研究双特异分子在溶液中的物理特性，用GE的AKTA chromatography进行凝胶排阻层析。所用的层析柱为HiLoad 16/600Superdex 200凝胶排阻层析柱，凝胶排阻层析所用的溶液为DPBS缓冲液(0.010M phosphate buffer,0.0027M KCl,0.14M NaCl,pH7.4)，凝胶排阻层析所用的流速为0.4ml/min。
图2B的凝胶排阻层析结果显示，所获得的双特异分子主要以单体形式存在，并且具有较高的纯度，无明显可见聚集。
实施例3.3特异性结合IL-1R和IL-6的双特异分子体外结合分析
包被重组人IL-6(SinoBiological)(100ng/孔)(PBS buffer，pH7.4)于96孔板，4℃孵育过夜；含2％脱脂奶粉的PBST(0.5％Tween-20in PBS)室温封闭1小时，经PBST洗3次后，分别加入梯度稀释的双特异分子(0.04nM-30nM)37℃孵育1h，PBST洗3次后，加入2％milk/PBST稀释的anti-human Fc-HRP(KPL,1:2500)二抗室温孵育1h，PBST洗5次后TMB(BioLegend)显色，Thermal VARIOSKAN FLASH plate reader在650nm波长下读数，数据用PrizmGraphpad软件的特定结合模型中的“non-linear regression”绘制和分析。
图7的ELISA结果显示，IL-1RA与aIL-6抗体重链或轻链的融合并不影响aIL-6抗体对IL-6的亲和力，靶向IL-1RA和IL-6的双特异分子对IL-6的亲和力与aIL-6抗体相似。
SEQUENCE LISTING
<110> 南通壹宸生物医药科技有限公司
<120> 一种双特异性分子及其制备与用途
<160> 76
<170> PatentIn version 3.5
<210> 1
<211> 1341
<212> DNA
<213> 人工序列
<400> 1
caggtgcagc tggtggagag cggaggtggc gtggtgcagc caggacgaag tctgcgcctg 60
agctgcgccg ccagcggctt caccttcagc gtgtacggca tgaactgggt gcgccaggcc 120
cccggcaagg gcctggagtg ggtggccatc atctggtacg acggcgacaa ccagtactac 180
gccgacagcg tgaagggccg cttcaccatc agccgcgaca acagcaagaa caccctgtac 240
ctgcagatga acggcctgcg cgccgaggac accgccgtgt actactgcgc ccgcgacctg 300
cgcaccggcc ccttcgacta ctggggccag ggcaccctgg tgaccgtgag cagcgcatca 360
acaaagggac caagcgtgtt tccactggcc ccctcaagca agagcacctc cggagggaca 420
gccgctctgg gatgtctggt gaaagactac ttccccgagc ctgtgactgt ctcttggaat 480
agtggcgctc tgacctccgg ggtgcacaca tttccagcag tcctgcagtc ctctggactg 540
tattctctga gttcagtggt caccgtgccc agctcctctc tgggcactca gacctacatc 600
tgcaatgtca accataagcc tagtaacaca aaagtggata agaaagtcga accaaagagc 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctc cagtcgccgg accgtcagtc 720
ttcctcttcc ctccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 900
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960
tgcaaggtct ccaacaaagg cctcccaagc tccatcgaga aaaccatctc caaagccaaa 1020
gggcagcccc gagaaccaca ggtgtacacc ctgcctccat cccgggatga gctgaccaag 1080
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320
ctctccctgt ctccgggtaa a 1341
<210> 2
<211> 447
<212> PRT
<213> 人工序列
<400> 2
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Val Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Trp Tyr Asp Gly Asp Asn Gln Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 3
<211> 642
<212> DNA
<213> 人工序列
<400> 3
gagatcgtgc tgacccagag ccccgacttc cagagcgtga cccccaagga gaaggtgacc 60
atcacctgcc gcgccagcca gagcatcggc agcagcctgc actggtacca gcagaagccc 120
gaccagagcc ccaagctgct gatcaagtac gccagccaga gcttcagcgg cgtgcccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcaacag cctggaggcc 240
gaggacgccg ccgcctacta ctgccaccag agcagcagcc tgcccttcac cttcggcccc 300
ggcaccaagg tggacatcaa gcgcacagtg gcagccccca gcgtcttcat ttttccccct 360
tccgatgaac agctgaagtc cggcactgct tctgtggtct gtctgctgaa caatttctat 420
cccagagagg ccaaggtgca gtggaaagtg gacaacgctc tgcagtccgg caacagccag 480
gagagtgtga ccgaacagga tagtaaggac agcacatatt ctctgtctag taccctgaca 540
ctgagtaagg cagattacga gaagcacaaa gtgtatgcct gcgaagtcac tcatcaggga 600
ctgtcaagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642
<210> 4
<211> 214
<212> PRT
<213> 人工序列
<400> 4
Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala
65 70 75 80
Glu Asp Ala Ala Ala Tyr Tyr Cys His Gln Ser Ser Ser Leu Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 5
<211> 1344
<212> DNA
<213> 人工序列
<400> 5
caggtgcagc tgcagcagtg gggcgccggc ctgctgaagc ccagcgagac cctgagcctg 60
acctgcgccg tgtacggcgg cagcttcagc gactactact ggagctggat ccgccagccc 120
cccggcaagg gcctggagtg gatcggcgag atcgaccaca gcggcagcac caactacaac 180
cccagcctga agagccgcgt gaccatcagc gtggacacca gcaagaacca gttcagcctg 240
aagctgagca gcgtgaccgc cgccgacacc gccgtgtact actgcgcccg cgccagcccc 300
agcagcggct ggaccctgga ctactggggc cagggcaccc tggtgaccgt gagcagcgca 360
tcaacaaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgactgtg ccctctagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgaacccaaa 660
tcttgcgaca aaactcacac atgcccaccg tgcccagcac ctccagtcgc cggaccgtca 720
gtcttcctct tccctccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcaagg tctccaacaa aggcctccca agctccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcctc catcccggga tgagctgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg taaa 1344
<210> 6
<211> 448
<212> PRT
<213> 人工序列
<400> 6
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Ser Pro Ser Ser Gly Trp Thr Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 7
<211> 639
<212> DNA
<213> 人工序列
<400> 7
cagagcgtgc tgacccagcc ccccagcgtg agcgtgagcc ccggccagac cgccagcatc 60
acctgcagcg gcgacaagct gggcgacaag ttcgccttct ggtaccagca gaagcccggc 120
cagagccccg tgctggtgat ctacctggac aacaagcgcc ccagcggcat ccccgagcgc 180
ttcagcggca gcaacagcgg caacaccgcc accctgacca tcagcggcac ccaggccctg 240
gacgaggccg actactactg ctacgcctgg gccgacacct acgaggtgtt cggcggcggc 300
accaaggtgg acatcaagcg cacagtggca gcccccagcg tcttcatttt tcccccttcc 360
gatgaacagc tgaagtccgg cactgcttct gtggtctgtc tgctgaacaa tttctatccc 420
agagaggcca aggtgcagtg gaaagtggac aacgctctgc agtccggcaa cagccaggag 480
agtgtgaccg aacaggatag taaggacagc acatattctc tgtctagtac cctgacactg 540
agtaaggcag attacgagaa gcacaaagtg tatgcctgcg aagtcactca tcagggactg 600
tcaagccccg tgaccaagag cttcaaccgg ggcgagtgt 639
<210> 8
<211> 213
<212> PRT
<213> 人工序列
<400> 8
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Phe Ala
20 25 30
Phe Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr
35 40 45
Leu Asp Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Leu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Tyr Ala Trp Ala Asp Thr Tyr Glu Val
85 90 95
Phe Gly Gly Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 9
<211> 1863
<212> DNA
<213> 人工序列
<400> 9
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg ggggtggcga agcagctgct 480
aaggaggcag ccgcaaagga agcagctgca aaggcaggag gccaggtgca gctggtggag 540
agcggaggtg gcgtggtgca gccaggacga agtctgcgcc tgagctgcgc cgccagcggc 600
ttcaccttca gcgtgtacgg catgaactgg gtgcgccagg cccccggcaa gggcctggag 660
tgggtggcca tcatctggta cgacggcgac aaccagtact acgccgacag cgtgaagggc 720
cgcttcacca tcagccgcga caacagcaag aacaccctgt acctgcagat gaacggcctg 780
cgcgccgagg acaccgccgt gtactactgc gcccgcgacc tgcgcaccgg ccccttcgac 840
tactggggcc agggcaccct ggtgaccgtg agcagcgcct ccaccaaggg cccatcggtc 900
ttccccctgg caccctcctc caagagcacc tctgggggca cagcggccct gggctgcctg 960
gtcaaggact acttccccga accggtgacg gtgtcgtgga actcaggcgc cctgaccagc 1020
ggcgtgcaca ccttcccggc tgtcctacag tcctcaggac tctactccct cagcagcgtg 1080
gtgactgtgc cctctagcag cttgggcacc cagacctaca tctgcaacgt gaatcacaag 1140
cccagcaaca ccaaggtgga caagaaagtt gaacccaaat cttgcgacaa aactcacaca 1200
tgcccaccgt gcccagcacc tccagtcgcc ggaccgtcag tcttcctctt ccctccaaaa 1260
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 1320
agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 1380
gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1440
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 1500
ggcctcccaa gctccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1560
caggtgtaca ccctgcctcc atcccgggat gagctgacca agaaccaggt cagcctgacc 1620
tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1680
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1740
tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1800
gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1860
aaa 1863
<210> 10
<211> 621
<212> PRT
<213> 人工序列
<400> 10
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Gly Glu Ala Ala Ala
145 150 155 160
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Gly Gly Gln Val
165 170 175
Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu
180 185 190
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Val Tyr Gly Met
195 200 205
Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ile
210 215 220
Ile Trp Tyr Asp Gly Asp Asn Gln Tyr Tyr Ala Asp Ser Val Lys Gly
225 230 235 240
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
245 250 255
Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
260 265 270
Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
275 280 285
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
290 295 300
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
305 310 315 320
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
325 330 335
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
340 345 350
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
355 360 365
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
370 375 380
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
385 390 395 400
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu
405 410 415
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
420 425 430
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
435 440 445
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
450 455 460
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
465 470 475 480
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
485 490 495
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
500 505 510
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
515 520 525
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
530 535 540
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
545 550 555 560
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
565 570 575
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
580 585 590
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
595 600 605
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
610 615 620
<210> 11
<211> 1164
<212> DNA
<213> 人工序列
<400> 11
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg ggggtggcga agcagctgct 480
aaggaggcag ccgcaaagga agcagctgca aaggcaggag gcgagatcgt gctgacccag 540
agccccgact tccagagcgt gacccccaag gagaaggtga ccatcacctg ccgcgccagc 600
cagagcatcg gcagcagcct gcactggtac cagcagaagc ccgaccagag ccccaagctg 660
ctgatcaagt acgccagcca gagcttcagc ggcgtgccca gccgcttcag cggcagcggc 720
agcggcaccg acttcaccct gaccatcaac agcctggagg ccgaggacgc cgccgcctac 780
tactgccacc agagcagcag cctgcccttc accttcggcc ccggcaccaa ggtggacatc 840
aagcgcacag tggcagcccc cagcgtcttc atttttcccc cttccgatga acagctgaag 900
tccggcactg cttctgtggt ctgtctgctg aacaatttct atcccagaga ggccaaggtg 960
cagtggaaag tggacaacgc tctgcagtcc ggcaacagcc aggagagtgt gaccgaacag 1020
gatagtaagg acagcacata ttctctgtct agtaccctga cactgagtaa ggcagattac 1080
gagaagcaca aagtgtatgc ctgcgaagtc actcatcagg gactgtcaag ccccgtgacc 1140
aagagcttca accggggcga gtgt 1164
<210> 12
<211> 388
<212> PRT
<213> 人工序列
<400> 12
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Gly Glu Ala Ala Ala
145 150 155 160
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Gly Gly Glu Ile
165 170 175
Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys Glu Lys
180 185 190
Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser Leu His
195 200 205
Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile Lys Tyr
210 215 220
Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
225 230 235 240
Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala Glu Asp
245 250 255
Ala Ala Ala Tyr Tyr Cys His Gln Ser Ser Ser Leu Pro Phe Thr Phe
260 265 270
Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser
275 280 285
Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala
290 295 300
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val
305 310 315 320
Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser
325 330 335
Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr
340 345 350
Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
355 360 365
Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn
370 375 380
Arg Gly Glu Cys
385
<210> 13
<211> 1926
<212> DNA
<213> 人工序列
<400> 13
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg gcggttctgg aagaggggct 480
gcacctgctg cagcacccgc aaaacaagaa gcagcggctc ccgctcccgc cgcaaaagca 540
gaagccccag ctgccgcgcc cgctgctaag gctggaggtt ccggacaggt gcagctggtg 600
gagagcggag gtggcgtggt gcagccagga cgaagtctgc gcctgagctg cgccgccagc 660
ggcttcacct tcagcgtgta cggcatgaac tgggtgcgcc aggcccccgg caagggcctg 720
gagtgggtgg ccatcatctg gtacgacggc gacaaccagt actacgccga cagcgtgaag 780
ggccgcttca ccatcagccg cgacaacagc aagaacaccc tgtacctgca gatgaacggc 840
ctgcgcgccg aggacaccgc cgtgtactac tgcgcccgcg acctgcgcac cggccccttc 900
gactactggg gccagggcac cctggtgacc gtgagcagcg catcaacaaa gggaccaagc 960
gtgtttccac tggccccctc cagcaagagc acctccggag ggacagccgc gctgggatgt 1020
ctggtgaaag actacttccc cgagcctgtg actgtctctt ggaatagtgg cgctctgacc 1080
tccggggtgc acacatttcc agcagtcctg cagtcctctg gactgtattc tctgagtagc 1140
gtggtcaccg tgcccagctc ctctctgggc actcagacct acatctgcaa tgtcaaccat 1200
aagcctagta acacaaaagt ggataagaaa gtcgaaccaa agagctgtga caaaactcac 1260
acatgcccac cgtgcccagc acctccagtc gccggaccgt cagtcttcct cttccctcca 1320
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 1380
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1440
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1500
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 1560
aaaggcctcc caagctccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1620
ccacaggtgt acaccctgcc tccatcccgg gatgagctga ccaagaacca ggtcagcctg 1680
acctgcctgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 1740
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1800
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1860
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1920
ggtaaa 1926
<210> 14
<211> 642
<212> PRT
<213> 人工序列
<400> 14
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Ser Gly Arg Gly Ala
145 150 155 160
Ala Pro Ala Ala Ala Pro Ala Lys Gln Glu Ala Ala Ala Pro Ala Pro
165 170 175
Ala Ala Lys Ala Glu Ala Pro Ala Ala Ala Pro Ala Ala Lys Ala Gly
180 185 190
Gly Ser Gly Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
195 200 205
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
210 215 220
Ser Val Tyr Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
225 230 235 240
Glu Trp Val Ala Ile Ile Trp Tyr Asp Gly Asp Asn Gln Tyr Tyr Ala
245 250 255
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
260 265 270
Thr Leu Tyr Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val
275 280 285
Tyr Tyr Cys Ala Arg Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly
290 295 300
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
305 310 315 320
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
325 330 335
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
340 345 350
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
355 360 365
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
370 375 380
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
385 390 395 400
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
405 410 415
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
420 425 430
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
435 440 445
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
450 455 460
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
465 470 475 480
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
485 490 495
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
500 505 510
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
515 520 525
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
530 535 540
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
545 550 555 560
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
565 570 575
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
580 585 590
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
595 600 605
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
610 615 620
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
625 630 635 640
Gly Lys
<210> 15
<211> 1227
<212> DNA
<213> 人工序列
<400> 15
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg gcggttctgg aagaggggct 480
gcacctgctg cagcacccgc aaaacaagaa gcagcggctc ccgctcccgc cgcaaaagca 540
gaagccccag ctgccgcgcc cgctgctaag gctggaggtt ccggagagat cgtgctgacc 600
cagagccccg acttccagag cgtgaccccc aaggagaagg tgaccatcac ctgccgcgcc 660
agccagagca tcggcagcag cctgcactgg taccagcaga agcccgacca gagccccaag 720
ctgctgatca agtacgccag ccagagcttc agcggcgtgc ccagccgctt cagcggcagc 780
ggcagcggca ccgacttcac cctgaccatc aacagcctgg aggccgagga cgccgccgcc 840
tactactgcc accagagcag cagcctgccc ttcaccttcg gccccggcac caaggtggac 900
atcaagcgca cagtggcagc ccccagcgtc ttcatttttc ccccttccga tgaacagctg 960
aagtccggca ctgcttctgt ggtctgtctg ctgaacaatt tctatcccag agaggccaag 1020
gtgcagtgga aagtggacaa cgctctgcag tccggcaaca gccaggagag tgtgaccgaa 1080
caggatagta aggacagcac atattctctg tctagtaccc tgacactgag taaggcagat 1140
tacgagaagc acaaagtgta tgcctgcgaa gtcactcatc agggactgtc aagccccgtg 1200
accaagagct tcaaccgggg cgagtgt 1227
<210> 16
<211> 409
<212> PRT
<213> 人工序列
<400> 16
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Ser Gly Arg Gly Ala
145 150 155 160
Ala Pro Ala Ala Ala Pro Ala Lys Gln Glu Ala Ala Ala Pro Ala Pro
165 170 175
Ala Ala Lys Ala Glu Ala Pro Ala Ala Ala Pro Ala Ala Lys Ala Gly
180 185 190
Gly Ser Gly Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val
195 200 205
Thr Pro Lys Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile
210 215 220
Gly Ser Ser Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys
225 230 235 240
Leu Leu Ile Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg
245 250 255
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser
260 265 270
Leu Glu Ala Glu Asp Ala Ala Ala Tyr Tyr Cys His Gln Ser Ser Ser
275 280 285
Leu Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr
290 295 300
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
305 310 315 320
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
325 330 335
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
340 345 350
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
355 360 365
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
370 375 380
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
385 390 395 400
Thr Lys Ser Phe Asn Arg Gly Glu Cys
405
<210> 17
<211> 1830
<212> DNA
<213> 人工序列
<400> 17
caggtgcagc tggtggagag cggaggtggc gtggtgcagc caggacgaag tctgcgcctg 60
agctgcgccg ccagcggctt caccttcagc gtgtacggca tgaactgggt gcgccaggcc 120
cccggcaagg gcctggagtg ggtggccatc atctggtacg acggcgacaa ccagtactac 180
gccgacagcg tgaagggccg cttcaccatc agccgcgaca acagcaagaa caccctgtac 240
ctgcagatga acggcctgcg cgccgaggac accgccgtgt actactgcgc ccgcgacctg 300
cgcaccggcc ccttcgacta ctggggccag ggcaccctgg tgaccgtgag cagcgcatca 360
acaaagggac caagcgtgtt tccactggcc ccctcaagca agagcacctc cggagggaca 420
gccgctctgg gatgtctggt gaaagactac ttccccgagc ctgtgactgt ctcttggaat 480
agtggcgctc tgacctccgg ggtgcacaca tttccagcag tcctgcagtc ctctggactg 540
tattctctga gttcagtggt caccgtgccc agctcctctc tgggcactca gacctacatc 600
tgcaatgtca accataagcc tagtaacaca aaagtggata agaaagtcga accaaagagc 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctc cagtcgccgg accgtcagtc 720
ttcctcttcc ctccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 900
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960
tgcaaggtct ccaacaaagg cctcccaagc tccatcgaga aaaccatctc caaagccaaa 1020
gggcagcccc gagaaccaca ggtgtacacc ctgcctccat cccgggatga gctgaccaag 1080
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320
ctctccctgt ctccgggtaa aggtggaggt ggctcaggtg gaggcggaag tatgcgcccc 1380
agcggccgca agagcagcaa gatgcaggcc ttccgcatct gggacgtgaa ccagaagacc 1440
ttctacctgc gcaacaacca gctggtggcc ggctacctgc agggccccaa cgtgaacctg 1500
gaggagaaga tcgacgtggt gcccatcgag ccccacgccc tgttcctggg catccacggc 1560
ggcaagatgt gcctgagctg cgtgaagagc ggcgacgaga cccgcctgca gctggaggcc 1620
gtgaacatca ccgacctgag cgagaaccgc aagcaggaca agcgcttcgc cttcatccgc 1680
agcgacagcg gccccaccac cagcttcgag agcgccgcct gccccggctg gttcctgtgc 1740
accgccatgg aggccgacca gcccgtgagc ctgaccaaca tgcccgacga gggcgtgatg 1800
gtgaccaagt tctacttcca ggaggacgag 1830
<210> 18
<211> 610
<212> PRT
<213> 人工序列
<400> 18
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Val Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Trp Tyr Asp Gly Asp Asn Gln Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Arg Pro Ser Gly Arg Lys
450 455 460
Ser Ser Lys Met Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr
465 470 475 480
Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro
485 490 495
Asn Val Asn Leu Glu Glu Lys Ile Asp Val Val Pro Ile Glu Pro His
500 505 510
Ala Leu Phe Leu Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val
515 520 525
Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr
530 535 540
Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg
545 550 555 560
Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly
565 570 575
Trp Phe Leu Cys Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr
580 585 590
Asn Met Pro Asp Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu
595 600 605
Asp Glu
610
<210> 19
<211> 1131
<212> DNA
<213> 人工序列
<400> 19
gagatcgtgc tgacccagag ccccgacttc cagagcgtga cccccaagga gaaggtgacc 60
atcacctgcc gcgccagcca gagcatcggc agcagcctgc actggtacca gcagaagccc 120
gaccagagcc ccaagctgct gatcaagtac gccagccaga gcttcagcgg cgtgcccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcaacag cctggaggcc 240
gaggacgccg ccgcctacta ctgccaccag agcagcagcc tgcccttcac cttcggcccc 300
ggcaccaagg tggacatcaa gcgcacagtg gcagccccca gcgtcttcat ttttccccct 360
tccgatgaac agctgaagtc cggcactgct tctgtggtct gtctgctgaa caatttctat 420
cccagagagg ccaaggtgca gtggaaagtg gacaacgctc tgcagtccgg caacagccag 480
gagagtgtga ccgaacagga tagtaaggac agcacatatt ctctgtctag taccctgaca 540
ctgagtaagg cagattacga gaagcacaaa gtgtatgcct gcgaagtcac tcatcaggga 600
ctgtcaagcc ccgtgaccaa gagcttcaac cggggcgagt gtggtggagg tggctcaggt 660
ggaggcggaa gtatgcgccc cagcggccgc aagagcagca agatgcaggc cttccgcatc 720
tgggacgtga accagaagac cttctacctg cgcaacaacc agctggtggc cggctacctg 780
cagggcccca acgtgaacct ggaggagaag atcgacgtgg tgcccatcga gccccacgcc 840
ctgttcctgg gcatccacgg cggcaagatg tgcctgagct gcgtgaagag cggcgacgag 900
acccgcctgc agctggaggc cgtgaacatc accgacctga gcgagaaccg caagcaggac 960
aagcgcttcg ccttcatccg cagcgacagc ggccccacca ccagcttcga gagcgccgcc 1020
tgccccggct ggttcctgtg caccgccatg gaggccgacc agcccgtgag cctgaccaac 1080
atgcccgacg agggcgtgat ggtgaccaag ttctacttcc aggaggacga g 1131
<210> 20
<211> 377
<212> PRT
<213> 人工序列
<400> 20
Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala
65 70 75 80
Glu Asp Ala Ala Ala Tyr Tyr Cys His Gln Ser Ser Ser Leu Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
225 230 235 240
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
245 250 255
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
260 265 270
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
275 280 285
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
290 295 300
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
305 310 315 320
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
325 330 335
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
340 345 350
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
355 360 365
Thr Lys Phe Tyr Phe Gln Glu Asp Glu
370 375
<210> 21
<211> 1161
<212> DNA
<213> 人工序列
<400> 21
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg ggggtggcga agcagctgct 480
aaggaggcag ccgcaaagga agcagctgca aaggcaggag gccagagcgt gctgacccag 540
ccccccagcg tgagcgtgag ccccggccag accgccagca tcacctgcag cggcgacaag 600
ctgggcgaca agttcgcctt ctggtaccag cagaagcccg gccagagccc cgtgctggtg 660
atctacctgg acaacaagcg ccccagcggc atccccgagc gcttcagcgg cagcaacagc 720
ggcaacaccg ccaccctgac catcagcggc acccaggccc tggacgaggc cgactactac 780
tgctacgcct gggccgacac ctacgaggtg ttcggcggcg gcaccaaggt ggacatcaag 840
cgcacagtgg cagcccccag cgtcttcatt tttccccctt ccgatgaaca gctgaagtcc 900
ggcactgctt ctgtggtctg tctgctgaac aatttctatc ccagagaggc caaggtgcag 960
tggaaagtgg acaacgctct gcagtccggc aacagccagg agagtgtgac cgaacaggat 1020
agtaaggaca gcacatattc tctgtctagt accctgacac tgagtaaggc agattacgag 1080
aagcacaaag tgtatgcctg cgaagtcact catcagggac tgtcaagccc cgtgaccaag 1140
agcttcaacc ggggcgagtg t 1161
<210> 22
<211> 387
<212> PRT
<213> 人工序列
<400> 22
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Gly Glu Ala Ala Ala
145 150 155 160
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Gly Gly Gln Ser
165 170 175
Val Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala
180 185 190
Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Phe Ala Phe Trp
195 200 205
Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr Leu Asp
210 215 220
Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser
225 230 235 240
Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Leu Asp Glu
245 250 255
Ala Asp Tyr Tyr Cys Tyr Ala Trp Ala Asp Thr Tyr Glu Val Phe Gly
260 265 270
Gly Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val
275 280 285
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
290 295 300
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
305 310 315 320
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val
325 330 335
Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
340 345 350
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu
355 360 365
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
370 375 380
Gly Glu Cys
385
<210> 23
<211> 1224
<212> DNA
<213> 人工序列
<400> 23
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg gcggttctgg aagaggggct 480
gcacctgctg cagcacccgc aaaacaagaa gcagcggctc ccgctcccgc cgcaaaagca 540
gaagccccag ctgccgcgcc cgctgctaag gctggaggtt ccggacagag cgtgctgacc 600
cagcccccca gcgtgagcgt gagccccggc cagaccgcca gcatcacctg cagcggcgac 660
aagctgggcg acaagttcgc cttctggtac cagcagaagc ccggccagag ccccgtgctg 720
gtgatctacc tggacaacaa gcgccccagc ggcatccccg agcgcttcag cggcagcaac 780
agcggcaaca ccgccaccct gaccatcagc ggcacccagg ccctggacga ggccgactac 840
tactgctacg cctgggccga cacctacgag gtgttcggcg gcggcaccaa ggtggacatc 900
aagcgcacag tggcagcccc cagcgtcttc atttttcccc cttccgatga acagctgaag 960
tccggcactg cttctgtggt ctgtctgctg aacaatttct atcccagaga ggccaaggtg 1020
cagtggaaag tggacaacgc tctgcagtcc ggcaacagcc aggagagtgt gaccgaacag 1080
gatagtaagg acagcacata ttctctgtct agtaccctga cactgagtaa ggcagattac 1140
gagaagcaca aagtgtatgc ctgcgaagtc actcatcagg gactgtcaag ccccgtgacc 1200
aagagcttca accggggcga gtgt 1224
<210> 24
<211> 408
<212> PRT
<213> 人工序列
<400> 24
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Ser Gly Arg Gly Ala
145 150 155 160
Ala Pro Ala Ala Ala Pro Ala Lys Gln Glu Ala Ala Ala Pro Ala Pro
165 170 175
Ala Ala Lys Ala Glu Ala Pro Ala Ala Ala Pro Ala Ala Lys Ala Gly
180 185 190
Gly Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Val Ser
195 200 205
Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp
210 215 220
Lys Phe Ala Phe Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu
225 230 235 240
Val Ile Tyr Leu Asp Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe
245 250 255
Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr
260 265 270
Gln Ala Leu Asp Glu Ala Asp Tyr Tyr Cys Tyr Ala Trp Ala Asp Thr
275 280 285
Tyr Glu Val Phe Gly Gly Gly Thr Lys Val Asp Ile Lys Arg Thr Val
290 295 300
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
305 310 315 320
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
325 330 335
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
340 345 350
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
355 360 365
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
370 375 380
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
385 390 395 400
Lys Ser Phe Asn Arg Gly Glu Cys
405
<210> 25
<211> 1371
<212> DNA
<213> 人工序列
<400> 25
gaagtccaac ttgtggaatc aggcggagga ctcgtgcaac ccggcggaag cctccgcctc 60
agttgcgctg cttcaggatt tactttctca aattactgga tgaattgggt tcgccaagcg 120
ccggggaaag gtttggagtg ggtagcagcg atcaaccagg acggatctga aaagtactat 180
gtaggctcag ttaaaggcag attcactatc tcaagggaca atgctaagaa ctctctttat 240
cttcaaatga actctttgcg agttgaagac accgctgttt actattgtgt aagagactat 300
tacgacatct tgaccgatta ttatatacac tactggtact ttgatctgtg gggaaggggt 360
accctcgtca cagtgtcctc agcatcaaca aagggaccaa gcgtgtttcc actggccccc 420
tcaagcaaga gcacctccgg agggacagcc gctctgggat gtctggtgaa agactacttc 480
cccgagcctg tgactgtctc ttggaatagt ggcgctctga cctccggggt gcacacattt 540
ccagcagtcc tgcagtcctc tggactgtat tctctgagtt cagtggtcac cgtgcccagc 600
tcctctctgg gcactcagac ctacatctgc aatgtcaacc ataagcctag taacacaaaa 660
gtggataaga aagtcgaacc aaagagctgt gacaaaactc acacatgccc accgtgccca 720
gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 780
ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 840
cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 900
ccgcgggagg agcagtacgc cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 960
caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 1020
cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 1080
ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 1140
ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1200
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 1260
accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 1320
gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a 1371
<210> 26
<211> 457
<212> PRT
<213> 人工序列
<400> 26
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Gly Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp
100 105 110
Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
130 135 140
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
180 185 190
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
195 200 205
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
210 215 220
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 27
<211> 645
<212> DNA
<213> 人工序列
<400> 27
gaaattgtgt tgacccaatc cccaggtact ctttctttgt caccgggtga gcgagccacc 60
ttgtcctgta gagcctccca gagcgtttca agttcatatt tggcatggta ccagcagaaa 120
cctggacaag cgccccgctt gttgatatat ggcgcttcta gccgagctac gggcatacca 180
gatagattct ccgggtccgg tagtggcacg gatttcacgc tcacgatctc acgccttgag 240
ccggaagact ttgcagttta ctattgtcag caatacgggt ctagcccctg cacattcggt 300
caagggactc gactggaaat taagcgcaca gtggcagccc ccagcgtctt catttttccc 360
ccttccgatg aacagctgaa gtccggcact gcttctgtgg tctgtctgct gaacaatttc 420
tatcccagag aggccaaggt gcagtggaaa gtggacaacg ctctgcagtc cggcaacagc 480
caggagagtg tgaccgaaca ggatagtaag gacagcacat attctctgtc tagtaccctg 540
acactgagta aggcagatta cgagaagcac aaagtgtatg cctgcgaagt cactcatcag 600
ggactgtcaa gccccgtgac caagagcttc aaccggggcg agtgt 645
<210> 28
<211> 215
<212> PRT
<213> 人工序列
<400> 28
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Cys Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 29
<211> 1890
<212> DNA
<213> 人工序列
<400> 29
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg ggggtggcga agcagctgct 480
aaggaggcag ccgcaaagga agcagctgca aaggcaggag gcgaagtcca acttgtggaa 540
tcaggcggag gactcgtgca acccggcgga agcctccgcc tcagttgcgc tgcttcagga 600
tttactttct caaattactg gatgaattgg gttcgccaag cgccggggaa aggtttggag 660
tgggtagcag cgatcaacca ggacggatct gaaaagtact atgtaggctc agttaaaggc 720
agattcacta tctcaaggga caatgctaag aactctcttt atcttcaaat gaactctttg 780
cgagttgaag acaccgctgt ttactattgt gtaagagact attacgacat cttgaccgat 840
tattatatac actactggta ctttgatctg tggggaaggg gtaccctcgt cacagtgtcc 900
tcagcctcca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 960
gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 1020
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 1080
tcaggactct actccctcag cagcgtggtg actgtgccct ctagcagctt gggcacccag 1140
acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgaa 1200
cccaaatctt gcgacaaaac tcacacatgc ccaccgtgcc cagcacctcc agtcgccgga 1260
ccgtcagtct tcctcttccc tccaaaaccc aaggacaccc tcatgatctc ccggacccct 1320
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 1380
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 1440
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 1500
gagtacaagt gcaaggtctc caacaaaggc ctcccaagct ccatcgagaa aaccatctcc 1560
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcctccatc ccgggatgag 1620
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1680
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1740
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1800
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1860
cagaagagcc tctccctgtc tccgggtaaa 1890
<210> 30
<211> 630
<212> PRT
<213> 人工序列
<400> 30
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Gly Glu Ala Ala Ala
145 150 155 160
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Gly Gly Glu Val
165 170 175
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
180 185 190
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr Trp Met
195 200 205
Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala
210 215 220
Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Gly Ser Val Lys Gly
225 230 235 240
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln
245 250 255
Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
260 265 270
Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp Tyr Phe
275 280 285
Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
290 295 300
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
305 310 315 320
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
325 330 335
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
340 345 350
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
355 360 365
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
370 375 380
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
385 390 395 400
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
405 410 415
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
420 425 430
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
435 440 445
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
450 455 460
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
465 470 475 480
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
485 490 495
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
500 505 510
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
515 520 525
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
530 535 540
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
545 550 555 560
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
565 570 575
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
580 585 590
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
595 600 605
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
610 615 620
Ser Leu Ser Pro Gly Lys
625 630
<210> 31
<211> 1167
<212> DNA
<213> 人工序列
<400> 31
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg ggggtggcga agcagctgct 480
aaggaggcag ccgcaaagga agcagctgca aaggcaggag gcgaaattgt gttgacccaa 540
tccccaggta ctctttcttt gtcaccgggt gagcgagcca ccttgtcctg tagagcctcc 600
cagagcgttt caagttcata tttggcatgg taccagcaga aacctggaca agcgccccgc 660
ttgttgatat atggcgcttc tagccgagct acgggcatac cagatagatt ctccgggtcc 720
ggtagtggca cggatttcac gctcacgatc tcacgccttg agccggaaga ctttgcagtt 780
tactattgtc agcaatacgg gtctagcccc tgcacattcg gtcaagggac tcgactggaa 840
attaagcgca cagtggcagc ccccagcgtc ttcatttttc ccccttccga tgaacagctg 900
aagtccggca ctgcttctgt ggtctgtctg ctgaacaatt tctatcccag agaggccaag 960
gtgcagtgga aagtggacaa cgctctgcag tccggcaaca gccaggagag tgtgaccgaa 1020
caggatagta aggacagcac atattctctg tctagtaccc tgacactgag taaggcagat 1080
tacgagaagc acaaagtgta tgcctgcgaa gtcactcatc agggactgtc aagccccgtg 1140
accaagagct tcaaccgggg cgagtgt 1167
<210> 32
<211> 389
<212> PRT
<213> 人工序列
<400> 32
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Gly Glu Ala Ala Ala
145 150 155 160
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Gly Gly Glu Ile
165 170 175
Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg
180 185 190
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu
195 200 205
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
210 215 220
Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser
225 230 235 240
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
245 250 255
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Cys Thr
260 265 270
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
275 280 285
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
290 295 300
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
305 310 315 320
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
325 330 335
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
340 345 350
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
355 360 365
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
370 375 380
Asn Arg Gly Glu Cys
385
<210> 33
<211> 1956
<212> DNA
<213> 人工序列
<400> 33
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg gcggttctgg aagaggggct 480
gcacctgctg cagcacccgc aaaacaagaa gcagcggctc ccgctcccgc cgcaaaagca 540
gaagccccag ctgccgcgcc cgctgctaag gctggaggtt ccggagaagt ccaacttgtg 600
gaatcaggcg gaggactcgt gcaacccggc ggaagcctcc gcctcagttg cgctgcttca 660
ggatttactt tctcaaatta ctggatgaat tgggttcgcc aagcgccggg gaaaggtttg 720
gagtgggtag cagcgatcaa ccaggacgga tctgaaaagt actatgtagg ctcagttaaa 780
ggcagattca ctatctcaag ggacaatgct aagaactctc tttatcttca aatgaactct 840
ttgcgagttg aagacaccgc tgtttactat tgtgtaagag actattacga catcttgacc 900
gattattata tacactactg gtactttgat ctgtggggaa ggggtaccct cgtcacagtg 960
tcctcagcct ccaccaaggg cccatcggtc ttccccctgg caccctcctc caagagcacc 1020
tctgggggca cagcggccct gggctgcctg gtcaaggact acttccccga accggtgacg 1080
gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 1140
tcctcaggac tctactccct cagcagcgtg gtgactgtgc cctctagcag cttgggcacc 1200
cagacctaca tctgcaacgt gaatcacaag cccagcaaca ccaaggtgga caagaaagtt 1260
gaacccaaat cttgcgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 1320
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 1380
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 1440
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1500
tacgccagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1560
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1620
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1680
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1740
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1800
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1860
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1920
tacacgcaga agagcctctc cctgtctccg ggtaaa 1956
<210> 34
<211> 652
<212> PRT
<213> 人工序列
<400> 34
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Ser Gly Arg Gly Ala
145 150 155 160
Ala Pro Ala Ala Ala Pro Ala Lys Gln Glu Ala Ala Ala Pro Ala Pro
165 170 175
Ala Ala Lys Ala Glu Ala Pro Ala Ala Ala Pro Ala Ala Lys Ala Gly
180 185 190
Gly Ser Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
195 200 205
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
210 215 220
Ser Asn Tyr Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
225 230 235 240
Glu Trp Val Ala Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val
245 250 255
Gly Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
260 265 270
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val
275 280 285
Tyr Tyr Cys Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile
290 295 300
His Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val
305 310 315 320
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
325 330 335
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
340 345 350
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
355 360 365
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
370 375 380
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
385 390 395 400
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
405 410 415
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
420 425 430
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
435 440 445
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
450 455 460
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
465 470 475 480
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
485 490 495
Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
500 505 510
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
515 520 525
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
530 535 540
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
545 550 555 560
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
565 570 575
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
580 585 590
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
595 600 605
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
610 615 620
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
625 630 635 640
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
645 650
<210> 35
<211> 1230
<212> DNA
<213> 人工序列
<400> 35
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg gcggttctgg aagaggggct 480
gcacctgctg cagcacccgc aaaacaagaa gcagcggctc ccgctcccgc cgcaaaagca 540
gaagccccag ctgccgcgcc cgctgctaag gctggaggtt ccggagaaat tgtgttgacc 600
caatccccag gtactctttc tttgtcaccg ggtgagcgag ccaccttgtc ctgtagagcc 660
tcccagagcg tttcaagttc atatttggca tggtaccagc agaaacctgg acaagcgccc 720
cgcttgttga tatatggcgc ttctagccga gctacgggca taccagatag attctccggg 780
tccggtagtg gcacggattt cacgctcacg atctcacgcc ttgagccgga agactttgca 840
gtttactatt gtcagcaata cgggtctagc ccctgcacat tcggtcaagg gactcgactg 900
gaaattaagc gcacagtggc agcccccagc gtcttcattt ttcccccttc cgatgaacag 960
ctgaagtccg gcactgcttc tgtggtctgt ctgctgaaca atttctatcc cagagaggcc 1020
aaggtgcagt ggaaagtgga caacgctctg cagtccggca acagccagga gagtgtgacc 1080
gaacaggata gtaaggacag cacatattct ctgtctagta ccctgacact gagtaaggca 1140
gattacgaga agcacaaagt gtatgcctgc gaagtcactc atcagggact gtcaagcccc 1200
gtgaccaaga gcttcaaccg gggcgagtgt 1230
<210> 36
<211> 410
<212> PRT
<213> 人工序列
<400> 36
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Ser Gly Arg Gly Ala
145 150 155 160
Ala Pro Ala Ala Ala Pro Ala Lys Gln Glu Ala Ala Ala Pro Ala Pro
165 170 175
Ala Ala Lys Ala Glu Ala Pro Ala Ala Ala Pro Ala Ala Lys Ala Gly
180 185 190
Gly Ser Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
195 200 205
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val
210 215 220
Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
225 230 235 240
Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp
245 250 255
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
260 265 270
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly
275 280 285
Ser Ser Pro Cys Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg
290 295 300
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
305 310 315 320
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
325 330 335
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
340 345 350
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
355 360 365
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
370 375 380
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
385 390 395 400
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
405 410
<210> 37
<211> 1347
<212> DNA
<213> 人工序列
<400> 37
gaggtgcagc tcgtagaatc cggtggaggt ttggttcagc ctgggggcag tctccggctg 60
tcatgtgcag cgagcggttt tacatttagc ccgttcgcta tgtcttgggt aaggcaagca 120
cctgggaaag ggttggaatg ggtcgctaag atcagtcctg gtggtagttg gacatactat 180
agcgataccg tcacgggaag gtttacgata tcccgcgata atgcaaagaa tagtctctac 240
cttcagatga atagtctgcg agctgaggat acagctgtgt attactgcgc tcggcaactc 300
tggggctatt acgcgttgga catttggggg cagggaacga ctgtaaccgt gtcttctgca 360
tcaacaaagg gaccaagcgt gtttccactg gccccctcaa gcaagagcac ctccggaggg 420
acagccgctc tgggatgtct ggtgaaagac tacttccccg agcctgtgac tgtctcttgg 480
aatagtggcg ctctgacctc cggggtgcac acatttccag cagtcctgca gtcctctgga 540
ctgtattctc tgagttcagt ggtcaccgtg cccagctcct ctctgggcac tcagacctac 600
atctgcaatg tcaaccataa gcctagtaac acaaaagtgg ataagaaagt cgaaccaaag 660
agctgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacgccagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaa 1347
<210> 38
<211> 449
<212> PRT
<213> 人工序列
<400> 38
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Lys Ile Ser Pro Gly Gly Ser Trp Thr Tyr Tyr Ser Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Leu Trp Gly Tyr Tyr Ala Leu Asp Ile Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 39
<211> 639
<212> DNA
<213> 人工序列
<400> 39
gagatagtcc tcactcagag tcccgctact ttgagcctct ccccaggaga gcgagccacc 60
ctttcttgtt ctgccagcat aagcgtgtca tacatgtact ggtatcagca aaaaccgggc 120
caagccccac gcttgctcat ttacgacatg agcaatctgg cgtccgggat accggctcgg 180
ttcagtggct ctgggtctgg gactgatttc acgcttacca taagctctct ggagcccgaa 240
gattttgcag tgtattactg tatgcaatgg tctgggtacc cttatacctt cggcggcggt 300
acgaaagttg aaatcaagcg cacagtggca gcccccagcg tcttcatttt tcccccttcc 360
gatgaacagc tgaagtccgg cactgcttct gtggtctgtc tgctgaacaa tttctatccc 420
agagaggcca aggtgcagtg gaaagtggac aacgctctgc agtccggcaa cagccaggag 480
agtgtgaccg aacaggatag taaggacagc acatattctc tgtctagtac cctgacactg 540
agtaaggcag attacgagaa gcacaaagtg tatgcctgcg aagtcactca tcagggactg 600
tcaagccccg tgaccaagag cttcaaccgg ggcgagtgt 639
<210> 40
<211> 213
<212> PRT
<213> 人工序列
<400> 40
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ile Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Met Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Met Gln Trp Ser Gly Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 41
<211> 1866
<212> DNA
<213> 人工序列
<400> 41
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg ggggtggcga agcagctgct 480
aaggaggcag ccgcaaagga agcagctgca aaggcaggag gcgaggtgca gctcgtagaa 540
tccggtggag gtttggttca gcctgggggc agtctccggc tgtcatgtgc agcgagcggt 600
tttacattta gcccgttcgc tatgtcttgg gtaaggcaag cacctgggaa agggttggaa 660
tgggtcgcta agatcagtcc tggtggtagt tggacatact atagcgatac cgtcacggga 720
aggtttacga tatcccgcga taatgcaaag aatagtctct accttcagat gaatagtctg 780
cgagctgagg atacagctgt gtattactgc gctcggcaac tctggggcta ttacgcgttg 840
gacatttggg ggcagggaac gactgtaacc gtgtcttctg cctccaccaa gggcccatcg 900
gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 960
ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 1020
agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 1080
gtggtgactg tgccctctag cagcttgggc acccagacct acatctgcaa cgtgaatcac 1140
aagcccagca acaccaaggt ggacaagaaa gttgaaccca aatcttgcga caaaactcac 1200
acatgcccac cgtgcccagc acctccagtc gccggaccgt cagtcttcct cttccctcca 1260
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 1320
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1380
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1440
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 1500
aaaggcctcc caagctccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1560
ccacaggtgt acaccctgcc tccatcccgg gatgagctga ccaagaacca ggtcagcctg 1620
acctgcctgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 1680
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1740
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1800
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1860
ggtaaa 1866
<210> 42
<211> 622
<212> PRT
<213> 人工序列
<400> 42
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Gly Glu Ala Ala Ala
145 150 155 160
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Gly Gly Glu Val
165 170 175
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
180 185 190
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Phe Ala Met
195 200 205
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Lys
210 215 220
Ile Ser Pro Gly Gly Ser Trp Thr Tyr Tyr Ser Asp Thr Val Thr Gly
225 230 235 240
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln
245 250 255
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
260 265 270
Gln Leu Trp Gly Tyr Tyr Ala Leu Asp Ile Trp Gly Gln Gly Thr Thr
275 280 285
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
290 295 300
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
305 310 315 320
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
325 330 335
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
340 345 350
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
355 360 365
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
370 375 380
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
385 390 395 400
Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
405 410 415
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
420 425 430
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
435 440 445
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
450 455 460
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
465 470 475 480
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
485 490 495
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
500 505 510
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
515 520 525
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
530 535 540
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
545 550 555 560
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
565 570 575
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
580 585 590
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
595 600 605
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
610 615 620
<210> 43
<211> 1161
<212> DNA
<213> 人工序列
<400> 43
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg ggggtggcga agcagctgct 480
aaggaggcag ccgcaaagga agcagctgca aaggcaggag gcgagatagt cctcactcag 540
agtcccgcta ctttgagcct ctccccagga gagcgagcca ccctttcttg ttctgccagc 600
ataagcgtgt catacatgta ctggtatcag caaaaaccgg gccaagcccc acgcttgctc 660
atttacgaca tgagcaatct ggcgtccggg ataccggctc ggttcagtgg ctctgggtct 720
gggactgatt tcacgcttac cataagctct ctggagcccg aagattttgc agtgtattac 780
tgtatgcaat ggtctgggta cccttatacc ttcggcggcg gtacgaaagt tgaaatcaag 840
cgcacagtgg cagcccccag cgtcttcatt tttccccctt ccgatgaaca gctgaagtcc 900
ggcactgctt ctgtggtctg tctgctgaac aatttctatc ccagagaggc caaggtgcag 960
tggaaagtgg acaacgctct gcagtccggc aacagccagg agagtgtgac cgaacaggat 1020
agtaaggaca gcacatattc tctgtctagt accctgacac tgagtaaggc agattacgag 1080
aagcacaaag tgtatgcctg cgaagtcact catcagggac tgtcaagccc cgtgaccaag 1140
agcttcaacc ggggcgagtg t 1161
<210> 44
<211> 387
<212> PRT
<213> 人工序列
<400> 44
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Gly Glu Ala Ala Ala
145 150 155 160
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Gly Gly Glu Ile
165 170 175
Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg
180 185 190
Ala Thr Leu Ser Cys Ser Ala Ser Ile Ser Val Ser Tyr Met Tyr Trp
195 200 205
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Met
210 215 220
Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
225 230 235 240
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe
245 250 255
Ala Val Tyr Tyr Cys Met Gln Trp Ser Gly Tyr Pro Tyr Thr Phe Gly
260 265 270
Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val
275 280 285
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
290 295 300
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
305 310 315 320
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val
325 330 335
Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
340 345 350
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu
355 360 365
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
370 375 380
Gly Glu Cys
385
<210> 45
<211> 1932
<212> DNA
<213> 人工序列
<400> 45
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg gcggttctgg aagaggggct 480
gcacctgctg cagcacccgc aaaacaagaa gcagcggctc ccgctcccgc cgcaaaagca 540
gaagccccag ctgccgcgcc cgctgctaag gctggaggtt ccggagaggt gcagctcgta 600
gaatccggtg gaggtttggt tcagcctggg ggcagtctcc ggctgtcatg tgcagcgagc 660
ggttttacat ttagcccgtt cgctatgtct tgggtaaggc aagcacctgg gaaagggttg 720
gaatgggtcg ctaagatcag tcctggtggt agttggacat actatagcga taccgtcacg 780
ggaaggttta cgatatcccg cgataatgca aagaatagtc tctaccttca gatgaatagt 840
ctgcgagctg aggatacagc tgtgtattac tgcgctcggc aactctgggg ctattacgcg 900
ttggacattt gggggcaggg aacgactgta accgtgtctt ctgcatcaac aaagggacca 960
agcgtgtttc cactggcccc ctcaagcaag agcacctccg gagggacagc cgctctggga 1020
tgtctggtga aagactactt ccccgagcct gtgactgtct cttggaatag tggcgctctg 1080
acctccgggg tgcacacatt tccagcagtc ctgcagtcct ctggactgta ttctctgagt 1140
tcagtggtca ccgtgcccag ctcctctctg ggcactcaga cctacatctg caatgtcaac 1200
cataagccta gtaacacaaa agtggataag aaagtcgaac caaagagctg tgacaaaact 1260
cacacatgcc caccgtgccc agcacctgaa ctcctggggg gaccgtcagt cttcctcttc 1320
cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 1380
gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 1440
gtgcataatg ccaagacaaa gccgcgggag gagcagtacg ccagcacgta ccgtgtggtc 1500
agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 1560
tccaacaaag ccctcccagc ccccatcgag aaaaccatct ccaaagccaa agggcagccc 1620
cgagaaccac aggtgtacac cctgccccca tcccgggagg agatgaccaa gaaccaggtc 1680
agcctgacct gcctggtcaa aggcttctat cccagcgaca tcgccgtgga gtgggagagc 1740
aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1800
ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1860
tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 1920
tctccgggta aa 1932
<210> 46
<211> 644
<212> PRT
<213> 人工序列
<400> 46
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Ser Gly Arg Gly Ala
145 150 155 160
Ala Pro Ala Ala Ala Pro Ala Lys Gln Glu Ala Ala Ala Pro Ala Pro
165 170 175
Ala Ala Lys Ala Glu Ala Pro Ala Ala Ala Pro Ala Ala Lys Ala Gly
180 185 190
Gly Ser Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
195 200 205
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
210 215 220
Ser Pro Phe Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
225 230 235 240
Glu Trp Val Ala Lys Ile Ser Pro Gly Gly Ser Trp Thr Tyr Tyr Ser
245 250 255
Asp Thr Val Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
260 265 270
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
275 280 285
Tyr Tyr Cys Ala Arg Gln Leu Trp Gly Tyr Tyr Ala Leu Asp Ile Trp
290 295 300
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
305 310 315 320
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
325 330 335
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
340 345 350
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
355 360 365
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
370 375 380
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
385 390 395 400
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
405 410 415
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
420 425 430
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
435 440 445
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
450 455 460
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
465 470 475 480
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr
485 490 495
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
500 505 510
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
515 520 525
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
530 535 540
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
545 550 555 560
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
565 570 575
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
580 585 590
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
595 600 605
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
610 615 620
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
625 630 635 640
Ser Pro Gly Lys
<210> 47
<211> 1224
<212> DNA
<213> 人工序列
<400> 47
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg gcggttctgg aagaggggct 480
gcacctgctg cagcacccgc aaaacaagaa gcagcggctc ccgctcccgc cgcaaaagca 540
gaagccccag ctgccgcgcc cgctgctaag gctggaggtt ccggagagat agtcctcact 600
cagagtcccg ctactttgag cctctcccca ggagagcgag ccaccctttc ttgttctgcc 660
agcataagcg tgtcatacat gtactggtat cagcaaaaac cgggccaagc cccacgcttg 720
ctcatttacg acatgagcaa tctggcgtcc gggataccgg ctcggttcag tggctctggg 780
tctgggactg atttcacgct taccataagc tctctggagc ccgaagattt tgcagtgtat 840
tactgtatgc aatggtctgg gtacccttat accttcggcg gcggtacgaa agttgaaatc 900
aagcgcacag tggcagcccc cagcgtcttc atttttcccc cttccgatga acagctgaag 960
tccggcactg cttctgtggt ctgtctgctg aacaatttct atcccagaga ggccaaggtg 1020
cagtggaaag tggacaacgc tctgcagtcc ggcaacagcc aggagagtgt gaccgaacag 1080
gatagtaagg acagcacata ttctctgtct agtaccctga cactgagtaa ggcagattac 1140
gagaagcaca aagtgtatgc ctgcgaagtc actcatcagg gactgtcaag ccccgtgacc 1200
aagagcttca accggggcga gtgt 1224
<210> 48
<211> 408
<212> PRT
<213> 人工序列
<400> 48
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Ser Gly Arg Gly Ala
145 150 155 160
Ala Pro Ala Ala Ala Pro Ala Lys Gln Glu Ala Ala Ala Pro Ala Pro
165 170 175
Ala Ala Lys Ala Glu Ala Pro Ala Ala Ala Pro Ala Ala Lys Ala Gly
180 185 190
Gly Ser Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu
195 200 205
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ile Ser Val
210 215 220
Ser Tyr Met Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
225 230 235 240
Leu Ile Tyr Asp Met Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe
245 250 255
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
260 265 270
Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Met Gln Trp Ser Gly Tyr
275 280 285
Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val
290 295 300
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
305 310 315 320
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
325 330 335
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
340 345 350
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
355 360 365
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
370 375 380
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
385 390 395 400
Lys Ser Phe Asn Arg Gly Glu Cys
405
<210> 49
<211> 459
<212> DNA
<213> 人工序列
<400> 49
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgag 459
<210> 50
<211> 153
<212> PRT
<213> 人工序列
<400> 50
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210> 51
<211> 1338
<212> DNA
<213> 人工序列
<400> 51
caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cgtctggatt caccttcagc aactatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcaggc atttggaatg atggaattaa taaataccat 180
gcacactccg tgaggggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcccgag agccgaggac acggctgtgt attactgtgc gagagcacgg 300
tctttcgact ggctattatt tgagttctgg ggccagggaa ccctggtcac cgtctctagt 360
gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 420
agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480
tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 540
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 600
tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 660
aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 720
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 780
gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 840
gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 900
gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 960
aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 1020
cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1080
caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 1140
gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 1200
ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320
tccctgtctc cgggtaaa 1338
<210> 52
<211> 446
<212> PRT
<213> 人工序列
<400> 52
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gly Ile Trp Asn Asp Gly Ile Asn Lys Tyr His Ala His Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Pro Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Arg Ser Phe Asp Trp Leu Leu Phe Glu Phe Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val
210 215 220
Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val
290 295 300
Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 53
<211> 645
<212> DNA
<213> 人工序列
<400> 53
gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctcc ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctccgct cactttcggc 300
ggagggacca aggtggagat caaacgcaca gtggcagccc ccagcgtctt catttttccc 360
ccttccgatg aacagctgaa gtccggcact gcttctgtgg tctgtctgct gaacaatttc 420
tatcccagag aggccaaggt gcagtggaaa gtggacaacg ctctgcagtc cggcaacagc 480
caggagagtg tgaccgaaca ggatagtaag gacagcacat attctctgtc tagtaccctg 540
acactgagta aggcagatta cgagaagcac aaagtgtatg cctgcgaagt cactcatcag 600
ggactgtcaa gccccgtgac caagagcttc aaccggggcg agtgt 645
<210> 54
<211> 215
<212> PRT
<213> 人工序列
<400> 54
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Pro Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 55
<211> 1338
<212> DNA
<213> 人工序列
<400> 55
caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag tgtctggatt caccttcagt aactatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagct atatggaatg atggagaaaa taaacaccat 180
gcaggctccg tgaggggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggacga 300
tattttgact ggttattatt tgagtattgg ggccagggaa ccctggtcac cgtctctagt 360
gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 420
agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480
tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 540
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 600
tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 660
aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 720
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 780
gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 840
gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 900
gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 960
aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 1020
cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1080
caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 1140
gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 1200
ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320
tccctgtctc cgggtaaa 1338
<210> 56
<211> 446
<212> PRT
<213> 人工序列
<400> 56
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Trp Asn Asp Gly Glu Asn Lys His His Ala Gly Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Tyr Phe Asp Trp Leu Leu Phe Glu Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val
210 215 220
Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val
290 295 300
Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 57
<211> 1332
<212> DNA
<213> 人工序列
<400> 57
gaggtgcagc tgatgcagtc tggagcagag gtgaaaaagc ccggggagtc tctgaagatc 60
tcctgtaagg gttctggata cagcttttcc ttccactgga tcgcctgggt gcgccagatg 120
cccgggaaag gcctggagtg gatggggatc atccatcctg gtgcctctga taccagatac 180
agcccgtcct tccaaggcca ggtcaccatc tcagccgaca actccaacag cgccacctac 240
ctgcagtgga gcagcctgaa ggcctcggac accgccatgt atttctgtgc gagacaaagg 300
gaactcgact actttgacta ctggggccag ggaaccctgg tcaccgtctc tagtgcctcc 360
accaagggcc catcggtctt ccccctggcg ccctgctcca ggagcacctc cgagagcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgctc tgaccagcgg cgtgcacacc ttcccagctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcaact tcggcaccca gacctacacc 600
tgcaacgtag atcacaagcc cagcaacacc aaggtggaca agacagttga gcgcaaatgt 660
tgtgtcgagt gcccaccgtg cccagcacca cctgtggcag gaccgtcagt cttcctcttc 720
cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac gtgcgtggtg 780
gtggacgtga gccacgaaga ccccgaggtc cagttcaact ggtacgtgga cggcgtggag 840
gtgcataatg ccaagacaaa gccacgggag gagcagttca acagcacgtt ccgtgtggtc 900
agcgtcctca ccgttgtgca ccaggactgg ctgaacggca aggagtacaa gtgcaaggtc 960
tccaacaaag gcctcccagc ccccatcgag aaaaccatct ccaaaaccaa agggcagccc 1020
cgagaaccac aggtgtacac cctgccccca tcccgggagg agatgaccaa gaaccaggtc 1080
agcctgacct gcctggtcaa aggcttctac cccagcgaca tcgccgtgga gtgggagagc 1140
aatgggcagc cggagaacaa ctacaagacc acacctccca tgctggactc cgacggctcc 1200
ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1260
tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 1320
tctccgggta aa 1332
<210> 58
<211> 444
<212> PRT
<213> 人工序列
<400> 58
Glu Val Gln Leu Met Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Phe His
20 25 30
Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile His Pro Gly Ala Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Asn Ser Asn Ser Ala Thr Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Phe Cys
85 90 95
Ala Arg Gln Arg Glu Leu Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys
210 215 220
Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr
290 295 300
Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 59
<211> 642
<212> DNA
<213> 人工序列
<400> 59
gaaattgtgc tgactcagtc tccagacttt cagtctgtga ctccaaagga gaaagtcacc 60
atcacctgcc gggccagtca gagcattggt agtagcttac actggtacca gcagaaacca 120
gatcagtctc caaagctcct catcaagtat gcttcccagt ccttctcagg ggtcccctcg 180
aggttcagtg gcagtggatc tgggacagat ttcaccctca ccatcaatag cctggaagct 240
gaagatgctg cagcgtatta ctgtcatcag agtagtagtt tacctctcac tttcggcgga 300
gggaccaagg tggagatcaa acgcacagtg gcagccccca gcgtcttcat ttttccccct 360
tccgatgaac agctgaagtc cggcactgct tctgtggtct gtctgctgaa caatttctat 420
cccagagagg ccaaggtgca gtggaaagtg gacaacgctc tgcagtccgg caacagccag 480
gagagtgtga ccgaacagga tagtaaggac agcacatatt ctctgtctag taccctgaca 540
ctgagtaagg cagattacga gaagcacaaa gtgtatgcct gcgaagtcac tcatcaggga 600
ctgtcaagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642
<210> 60
<211> 214
<212> PRT
<213> 人工序列
<400> 60
Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala
65 70 75 80
Glu Asp Ala Ala Ala Tyr Tyr Cys His Gln Ser Ser Ser Leu Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 61
<211> 1848
<212> DNA
<213> 人工序列
<400> 61
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg gaggcagcgg gggaagcggc 480
ggcggagggt ctggaggagg gggcagtcag gtgcagctgg tggagagcgg aggtggcgtg 540
gtgcagccag gacgaagtct gcgcctgagc tgcgccgcca gcggcttcac cttcagcgtg 600
tacggcatga actgggtgcg ccaggccccc ggcaagggcc tggagtgggt ggccatcatc 660
tggtacgacg gcgacaacca gtactacgcc gacagcgtga agggccgctt caccatcagc 720
cgcgacaaca gcaagaacac cctgtacctg cagatgaacg gcctgcgcgc cgaggacacc 780
gccgtgtact actgcgcccg cgacctgcgc accggcccct tcgactactg gggccagggc 840
accctggtga ccgtgagcag cgcctccacc aagggcccat cggtcttccc cctggcaccc 900
tcctccaaga gcacctctgg gggcacagcg gccctgggct gcctggtcaa ggactacttc 960
cccgaaccgg tgacggtgtc gtggaactca ggcgccctga ccagcggcgt gcacaccttc 1020
ccggctgtcc tacagtcctc aggactctac tccctcagca gcgtggtgac tgtgccctct 1080
agcagcttgg gcacccagac ctacatctgc aacgtgaatc acaagcccag caacaccaag 1140
gtggacaaga aagttgaacc caaatcttgc gacaaaactc acacatgccc accgtgccca 1200
gcacctccag tcgccggacc gtcagtcttc ctcttccctc caaaacccaa ggacaccctc 1260
atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 1320
gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 1380
cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1440
gactggctga atggcaagga gtacaagtgc aaggtctcca acaaaggcct cccaagctcc 1500
atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1560
cctccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1620
ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1680
aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1740
gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1800
ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1848
<210> 62
<211> 616
<212> PRT
<213> 人工序列
<400> 62
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Ser Gly Gly Ser Gly
145 150 155 160
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser
165 170 175
Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala
180 185 190
Ala Ser Gly Phe Thr Phe Ser Val Tyr Gly Met Asn Trp Val Arg Gln
195 200 205
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ile Ile Trp Tyr Asp Gly
210 215 220
Asp Asn Gln Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
225 230 235 240
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Gly Leu Arg
245 250 255
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Leu Arg Thr Gly
260 265 270
Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
275 280 285
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
290 295 300
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
305 310 315 320
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
325 330 335
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
340 345 350
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
355 360 365
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
370 375 380
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
385 390 395 400
Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
405 410 415
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
420 425 430
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
435 440 445
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
450 455 460
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
465 470 475 480
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
485 490 495
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
500 505 510
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
515 520 525
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
530 535 540
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
545 550 555 560
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
565 570 575
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
580 585 590
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
595 600 605
Ser Leu Ser Leu Ser Pro Gly Lys
610 615
<210> 63
<211> 1848
<212> DNA
<213> 人工序列
<400> 63
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg gcggaggcgg atccggaggc 480
ggaggttccg gcgggggtgg gagcgggcag gtgcagctgg tggagagcgg aggtggcgtg 540
gtgcagccag gacgaagtct gcgcctgagc tgcgccgcca gcggcttcac cttcagcgtg 600
tacggcatga actgggtgcg ccaggccccc ggcaagggcc tggagtgggt ggccatcatc 660
tggtacgacg gcgacaacca gtactacgcc gacagcgtga agggccgctt caccatcagc 720
cgcgacaaca gcaagaacac cctgtacctg cagatgaacg gcctgcgcgc cgaggacacc 780
gccgtgtact actgcgcccg cgacctgcgc accggcccct tcgactactg gggccagggc 840
accctggtga ccgtgagcag cgcatcaaca aagggaccaa gcgtgtttcc actggccccc 900
tccagcaaga gcacctccgg agggacagcc gcgctgggat gtctggtgaa agactacttc 960
cccgagcctg tgactgtctc ttggaatagt ggcgctctga cctccggggt gcacacattt 1020
ccagcagtcc tgcagtcctc tggactgtat tctctgagta gcgtggtcac cgtgcccagc 1080
tcctctctgg gcactcagac ctacatctgc aatgtcaacc ataagcctag taacacaaaa 1140
gtggataaga aagtcgaacc aaagagctgt gacaaaactc acacatgccc accgtgccca 1200
gcacctccag tcgccggacc gtcagtcttc ctcttccctc caaaacccaa ggacaccctc 1260
atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 1320
gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 1380
cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1440
gactggctga atggcaagga gtacaagtgc aaggtctcca acaaaggcct cccaagctcc 1500
atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1560
cctccatccc gggatgagct gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1620
ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1680
aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1740
gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1800
ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1848
<210> 64
<211> 616
<212> PRT
<213> 人工序列
<400> 64
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gln Val Gln Leu Val Glu Ser
165 170 175
Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala
180 185 190
Ala Ser Gly Phe Thr Phe Ser Val Tyr Gly Met Asn Trp Val Arg Gln
195 200 205
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ile Ile Trp Tyr Asp Gly
210 215 220
Asp Asn Gln Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
225 230 235 240
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Gly Leu Arg
245 250 255
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Leu Arg Thr Gly
260 265 270
Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
275 280 285
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
290 295 300
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
305 310 315 320
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
325 330 335
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
340 345 350
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
355 360 365
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
370 375 380
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
385 390 395 400
Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
405 410 415
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
420 425 430
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
435 440 445
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
450 455 460
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
465 470 475 480
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
485 490 495
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
500 505 510
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
515 520 525
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
530 535 540
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
545 550 555 560
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
565 570 575
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
580 585 590
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
595 600 605
Ser Leu Ser Leu Ser Pro Gly Lys
610 615
<210> 65
<211> 1878
<212> DNA
<213> 人工序列
<400> 65
caggtgcagc tgcagcagtg gggcgccggc ctgctgaagc ccagcgagac cctgagcctg 60
acctgcgccg tgtacggcgg cagcttcagc gactactact ggagctggat ccgccagccc 120
cccggcaagg gcctggagtg gatcggcgag atcgaccaca gcggcagcac caactacaac 180
cccagcctga agagccgcgt gaccatcagc gtggacacca gcaagaacca gttcagcctg 240
aagctgagca gcgtgaccgc cgccgacacc gccgtgtact actgcgcccg cgccagcccc 300
agcagcggct ggaccctgga ctactggggc cagggcaccc tggtgaccgt gagcagcgca 360
tcaacaaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgactgtg ccctctagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgaacccaaa 660
tcttgcgaca aaactcacac atgcccaccg tgcccagcac ctccagtcgc cggaccgtca 720
gtcttcctct tccctccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcaagg tctccaacaa aggcctccca agctccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcctc catcccggga tgagctgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg taaaggcgga ggcggatccg gaggcggagg ttccggcggg 1380
ggtgggagcg gcggcggagg gtctggagga gggggcagta tgcgccccag cggccgcaag 1440
agcagcaaga tgcaggcctt ccgcatctgg gacgtgaacc agaagacctt ctacctgcgc 1500
aacaaccagc tggtggccgg ctacctgcag ggccccaacg tgaacctgga ggagaagatc 1560
gacgtggtgc ccatcgagcc ccacgccctg ttcctgggca tccacggcgg caagatgtgc 1620
ctgagctgcg tgaagagcgg cgacgagacc cgcctgcagc tggaggccgt gaacatcacc 1680
gacctgagcg agaaccgcaa gcaggacaag cgcttcgcct tcatccgcag cgacagcggc 1740
cccaccacca gcttcgagag cgccgcctgc cccggctggt tcctgtgcac cgccatggag 1800
gccgaccagc ccgtgagcct gaccaacatg cccgacgagg gcgtgatggt gaccaagttc 1860
tacttccagg aggacgag 1878
<210> 66
<211> 626
<212> PRT
<213> 人工序列
<400> 66
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Ser Pro Ser Ser Gly Trp Thr Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
450 455 460
Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Arg Pro Ser Gly Arg Lys
465 470 475 480
Ser Ser Lys Met Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr
485 490 495
Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro
500 505 510
Asn Val Asn Leu Glu Glu Lys Ile Asp Val Val Pro Ile Glu Pro His
515 520 525
Ala Leu Phe Leu Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val
530 535 540
Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr
545 550 555 560
Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg
565 570 575
Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly
580 585 590
Trp Phe Leu Cys Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr
595 600 605
Asn Met Pro Asp Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu
610 615 620
Asp Glu
625
<210> 67
<211> 1173
<212> DNA
<213> 人工序列
<400> 67
atgcgcccca gcggccgcaa gagcagcaag atgcaggcct tccgcatctg ggacgtgaac 60
cagaagacct tctacctgcg caacaaccag ctggtggccg gctacctgca gggccccaac 120
gtgaacctgg aggagaagat cgacgtggtg cccatcgagc cccacgccct gttcctgggc 180
atccacggcg gcaagatgtg cctgagctgc gtgaagagcg gcgacgagac ccgcctgcag 240
ctggaggccg tgaacatcac cgacctgagc gagaaccgca agcaggacaa gcgcttcgcc 300
ttcatccgca gcgacagcgg ccccaccacc agcttcgaga gcgccgcctg ccccggctgg 360
ttcctgtgca ccgccatgga ggccgaccag cccgtgagcc tgaccaacat gcccgacgag 420
ggcgtgatgg tgaccaagtt ctacttccag gaggacgagg gcggaggcgg atccggaggc 480
ggaggttccg gcgggggtgg gagcggcggc ggagggtctg gaggaggggg cagtcagagc 540
gtgctgaccc agccccccag cgtgagcgtg agccccggcc agaccgccag catcacctgc 600
agcggcgaca agctgggcga caagttcgcc ttctggtacc agcagaagcc cggccagagc 660
cccgtgctgg tgatctacct ggacaacaag cgccccagcg gcatccccga gcgcttcagc 720
ggcagcaaca gcggcaacac cgccaccctg accatcagcg gcacccaggc cctggacgag 780
gccgactact actgctacgc ctgggccgac acctacgagg tgttcggcgg cggcaccaag 840
gtggacatca agcgcacagt ggcagccccc agcgtcttca tttttccccc ttccgatgaa 900
cagctgaagt ccggcactgc ttctgtggtc tgtctgctga acaatttcta tcccagagag 960
gccaaggtgc agtggaaagt ggacaacgct ctgcagtccg gcaacagcca ggagagtgtg 1020
accgaacagg atagtaagga cagcacatat tctctgtcta gtaccctgac actgagtaag 1080
gcagattacg agaagcacaa agtgtatgcc tgcgaagtca ctcatcaggg actgtcaagc 1140
cccgtgacca agagcttcaa ccggggcgag tgt 1173
<210> 68
<211> 391
<212> PRT
<213> 人工序列
<400> 68
Met Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile
1 5 10 15
Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val
20 25 30
Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp
35 40 45
Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
50 55 60
Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
65 70 75 80
Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
85 90 95
Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
100 105 110
Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
115 120 125
Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
130 135 140
Thr Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
165 170 175
Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro
180 185 190
Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys
195 200 205
Phe Ala Phe Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val
210 215 220
Ile Tyr Leu Asp Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser
225 230 235 240
Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln
245 250 255
Ala Leu Asp Glu Ala Asp Tyr Tyr Cys Tyr Ala Trp Ala Asp Thr Tyr
260 265 270
Glu Val Phe Gly Gly Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala
275 280 285
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
290 295 300
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
305 310 315 320
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
325 330 335
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
340 345 350
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
355 360 365
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
370 375 380
Ser Phe Asn Arg Gly Glu Cys
385 390
<210> 69
<211> 2187
<212> DNA
<213> 人工序列
<400> 69
gaagtccaac tgatgcaaag cggagctgaa gttaagaagc ccggagagtc attgaaaata 60
agttgtaagg ggtccgggta ctccttcagt ttccattgga tcgcatgggt gcgacaaatg 120
ccgggaaaag gactcgagtg gatggggatt atccatcctg gagcctcaga cacccgctat 180
tctccgagct ttcaaggtca agtgacaatt tccgcagata acagtaattc cgcgacctat 240
ttgcaatggt caagtctcaa ggccagtgat acggcgatgt acttctgcgc cagacaacgg 300
gaacttgatt acttcgacta ctggggacag gggacccttg taacagttag ctccggtggc 360
ggtggctcgg gcggtggtgg gtcgggtggc ggcggatctg agatagtgct cacgcaatca 420
cccgattttc aatctgtcac gcctaaagag aaggtcacta taacctgtag agcgagtcag 480
tcaataggct cctcacttca ctggtaccag caaaaacctg accaaagccc caaattgctc 540
ataaagtacg ccagccaatc cttcagtgga gtgccaagca ggttctccgg gtctggctct 600
ggtactgact tcactttgac cattaacagc ctcgaggccg aagacgctgc agcctactat 660
tgtcaccagt catccagcct tccgctgact ttcggtggtg gtacaaaggt agagattaag 720
ggcggttctg gaagaggggc tgcacctgct gcagcacccg caaaacaaga agcagcggct 780
cccgctcccg ccgcaaaagc agaagcccca gctgccgcgc ccgctgctaa ggctggaggt 840
tccggacagg tgcagctggt ggagagcgga ggtggcgtgg tgcagccagg acgaagtctg 900
cgcctgagct gcgccgccag cggcttcacc ttcagcgtgt acggcatgaa ctgggtgcgc 960
caggcccccg gcaagggcct ggagtgggtg gccatcatct ggtacgacgg cgacaaccag 1020
tactacgccg acagcgtgaa gggccgcttc accatcagcc gcgacaacag caagaacacc 1080
ctgtacctgc agatgaacgg cctgcgcgcc gaggacaccg ccgtgtacta ctgcgcccgc 1140
gacctgcgca ccggcccctt cgactactgg ggccagggca ccctggtgac cgtgagcagc 1200
gcatcaacaa agggaccaag cgtgtttcca ctggccccct ccagcaagag cacctccgga 1260
gggacagccg cgctgggatg tctggtgaaa gactacttcc ccgagcctgt gactgtctct 1320
tggaatagtg gcgctctgac ctccggggtg cacacatttc cagcagtcct gcagtcctct 1380
ggactgtatt ctctgagtag cgtggtcacc gtgcccagct cctctctggg cactcagacc 1440
tacatctgca atgtcaacca taagcctagt aacacaaaag tggataagaa agtcgaacca 1500
aagagctgtg acaaaactca cacatgccca ccgtgcccag cacctccagt cgccggaccg 1560
tcagtcttcc tcttccctcc aaaacccaag gacaccctca tgatctcccg gacccctgag 1620
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 1680
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 1740
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 1800
tacaagtgca aggtctccaa caaaggcctc ccaagctcca tcgagaaaac catctccaaa 1860
gccaaagggc agccccgaga accacaggtg tacaccctgc ctccatcccg ggatgagctg 1920
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1980
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 2040
gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 2100
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 2160
aagagcctct ccctgtctcc gggtaaa 2187
<210> 70
<211> 729
<212> PRT
<213> 人工序列
<400> 70
Glu Val Gln Leu Met Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Phe His
20 25 30
Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile His Pro Gly Ala Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Asn Ser Asn Ser Ala Thr Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Phe Cys
85 90 95
Ala Arg Gln Arg Glu Leu Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln
130 135 140
Ser Val Thr Pro Lys Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln
145 150 155 160
Ser Ile Gly Ser Ser Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser
165 170 175
Pro Lys Leu Leu Ile Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro
180 185 190
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
195 200 205
Asn Ser Leu Glu Ala Glu Asp Ala Ala Ala Tyr Tyr Cys His Gln Ser
210 215 220
Ser Ser Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
225 230 235 240
Gly Gly Ser Gly Arg Gly Ala Ala Pro Ala Ala Ala Pro Ala Lys Gln
245 250 255
Glu Ala Ala Ala Pro Ala Pro Ala Ala Lys Ala Glu Ala Pro Ala Ala
260 265 270
Ala Pro Ala Ala Lys Ala Gly Gly Ser Gly Gln Val Gln Leu Val Glu
275 280 285
Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys
290 295 300
Ala Ala Ser Gly Phe Thr Phe Ser Val Tyr Gly Met Asn Trp Val Arg
305 310 315 320
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ile Ile Trp Tyr Asp
325 330 335
Gly Asp Asn Gln Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
340 345 350
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Gly Leu
355 360 365
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Leu Arg Thr
370 375 380
Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
385 390 395 400
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
405 410 415
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
420 425 430
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
435 440 445
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
450 455 460
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
465 470 475 480
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
485 490 495
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
500 505 510
Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
565 570 575
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys
725
<210> 71
<211> 2109
<212> DNA
<213> 人工序列
<400> 71
gaagtccaac tgatgcaaag cggagctgaa gttaagaagc ccggagagtc attgaaaata 60
agttgtaagg ggtccgggta ctccttcagt ttccattgga tcgcatgggt gcgacaaatg 120
ccgggaaaag gactcgagtg gatggggatt atccatcctg gagcctcaga cacccgctat 180
tctccgagct ttcaaggtca agtgacaatt tccgcagata acagtaattc cgcgacctat 240
ttgcaatggt caagtctcaa ggccagtgat acggcgatgt acttctgcgc cagacaacgg 300
gaacttgatt acttcgacta ctggggacag gggacccttg taacagttag ctccggtggc 360
ggtggctcgg gcggtggtgg gtcgggtggc ggcggatctg agatagtgct cacgcaatca 420
cccgattttc aatctgtcac gcctaaagag aaggtcacta taacctgtag agcgagtcag 480
tcaataggct cctcacttca ctggtaccag caaaaacctg accaaagccc caaattgctc 540
ataaagtacg ccagccaatc cttcagtgga gtgccaagca ggttctccgg gtctggctct 600
ggtactgact tcactttgac cattaacagc ctcgaggccg aagacgctgc agcctactat 660
tgtcaccagt catccagcct tccgctgact ttcggtggtg gtacaaaggt agagattaag 720
ggaggcagcg ggggaagcgg cggcggaggg tctggaggag ggggcagtca ggtgcagctg 780
gtggagagcg gaggtggcgt ggtgcagcca ggacgaagtc tgcgcctgag ctgcgccgcc 840
agcggcttca ccttcagcgt gtacggcatg aactgggtgc gccaggcccc cggcaagggc 900
ctggagtggg tggccatcat ctggtacgac ggcgacaacc agtactacgc cgacagcgtg 960
aagggccgct tcaccatcag ccgcgacaac agcaagaaca ccctgtacct gcagatgaac 1020
ggcctgcgcg ccgaggacac cgccgtgtac tactgcgccc gcgacctgcg caccggcccc 1080
ttcgactact ggggccaggg caccctggtg accgtgagca gcgcatcaac aaagggacca 1140
agcgtgtttc cactggcccc ctccagcaag agcacctccg gagggacagc cgcgctggga 1200
tgtctggtga aagactactt ccccgagcct gtgactgtct cttggaatag tggcgctctg 1260
acctccgggg tgcacacatt tccagcagtc ctgcagtcct ctggactgta ttctctgagt 1320
agcgtggtca ccgtgcccag ctcctctctg ggcactcaga cctacatctg caatgtcaac 1380
cataagccta gtaacacaaa agtggataag aaagtcgaac caaagagctg tgacaaaact 1440
cacacatgcc caccgtgccc agcacctcca gtcgccggac cgtcagtctt cctcttccct 1500
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 1560
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1620
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1680
gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 1740
aacaaaggcc tcccaagctc catcgagaaa accatctcca aagccaaagg gcagccccga 1800
gaaccacagg tgtacaccct gcctccatcc cgggatgagc tgaccaagaa ccaggtcagc 1860
ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1920
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1980
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 2040
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 2100
ccgggtaaa 2109
<210> 72
<211> 703
<212> PRT
<213> 人工序列
<400> 72
Glu Val Gln Leu Met Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Phe His
20 25 30
Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile His Pro Gly Ala Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Asn Ser Asn Ser Ala Thr Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Phe Cys
85 90 95
Ala Arg Gln Arg Glu Leu Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln
130 135 140
Ser Val Thr Pro Lys Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln
145 150 155 160
Ser Ile Gly Ser Ser Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser
165 170 175
Pro Lys Leu Leu Ile Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro
180 185 190
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
195 200 205
Asn Ser Leu Glu Ala Glu Asp Ala Ala Ala Tyr Tyr Cys His Gln Ser
210 215 220
Ser Ser Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
225 230 235 240
Gly Gly Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
260 265 270
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Val Tyr
275 280 285
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Ile Ile Trp Tyr Asp Gly Asp Asn Gln Tyr Tyr Ala Asp Ser Val
305 310 315 320
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
325 330 335
Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Ala Arg Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
370 375 380
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
385 390 395 400
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
405 410 415
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
420 425 430
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
435 440 445
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
450 455 460
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
465 470 475 480
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
690 695 700
<210> 73
<211> 2187
<212> DNA
<213> 人工序列
<400> 73
caggtgcagc tggtggagag cggaggtggc gtggtgcagc caggacgaag tctgcgcctg 60
agctgcgccg ccagcggctt caccttcagc gtgtacggca tgaactgggt gcgccaggcc 120
cccggcaagg gcctggagtg ggtggccatc atctggtacg acggcgacaa ccagtactac 180
gccgacagcg tgaagggccg cttcaccatc agccgcgaca acagcaagaa caccctgtac 240
ctgcagatga acggcctgcg cgccgaggac accgccgtgt actactgcgc ccgcgacctg 300
cgcaccggcc ccttcgacta ctggggccag ggcaccctgg tgaccgtgag cagcgcatca 360
acaaagggac caagcgtgtt tccactggcc ccctccagca agagcacctc cggagggaca 420
gccgcgctgg gatgtctggt gaaagactac ttccccgagc ctgtgactgt ctcttggaat 480
agtggcgctc tgacctccgg ggtgcacaca tttccagcag tcctgcagtc ctctggactg 540
tattctctga gtagcgtggt caccgtgccc agctcctctc tgggcactca gacctacatc 600
tgcaatgtca accataagcc tagtaacaca aaagtggata agaaagtcga accaaagagc 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctc cagtcgccgg accgtcagtc 720
ttcctcttcc ctccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 900
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960
tgcaaggtct ccaacaaagg cctcccaagc tccatcgaga aaaccatctc caaagccaaa 1020
gggcagcccc gagaaccaca ggtgtacacc ctgcctccat cccgggatga gctgaccaag 1080
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320
ctctccctgt ctccgggtaa aggcggttct ggaagagggg ctgcacctgc tgcagcaccc 1380
gcaaaacaag aagcagcggc tcccgctccc gccgcaaaag cagaagcccc agctgccgcg 1440
cccgctgcta aggctggagg ttccggagaa gtccaactga tgcaaagcgg agctgaagtt 1500
aagaagcccg gagagtcatt gaaaataagt tgtaaggggt ccgggtactc cttcagtttc 1560
cattggatcg catgggtgcg acaaatgccg ggaaaaggac tcgagtggat ggggattatc 1620
catcctggag cctcagacac ccgctattct ccgagctttc aaggtcaagt gacaatttcc 1680
gcagataaca gtaattccgc gacctatttg caatggtcaa gtctcaaggc cagtgatacg 1740
gcgatgtact tctgcgccag acaacgggaa cttgattact tcgactactg gggacagggg 1800
acccttgtaa cagttagctc cggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 1860
ggatctgaga tagtgctcac gcaatcaccc gattttcaat ctgtcacgcc taaagagaag 1920
gtcactataa cctgtagagc gagtcagtca ataggctcct cacttcactg gtaccagcaa 1980
aaacctgacc aaagccccaa attgctcata aagtacgcca gccaatcctt cagtggagtg 2040
ccaagcaggt tctccgggtc tggctctggt actgacttca ctttgaccat taacagcctc 2100
gaggccgaag acgctgcagc ctactattgt caccagtcat ccagccttcc gctgactttc 2160
ggtggtggta caaaggtaga gattaag 2187
<210> 74
<211> 729
<212> PRT
<213> 人工序列
<400> 74
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Val Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Trp Tyr Asp Gly Asp Asn Gln Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly
435 440 445
Gly Ser Gly Arg Gly Ala Ala Pro Ala Ala Ala Pro Ala Lys Gln Glu
450 455 460
Ala Ala Ala Pro Ala Pro Ala Ala Lys Ala Glu Ala Pro Ala Ala Ala
465 470 475 480
Pro Ala Ala Lys Ala Gly Gly Ser Gly Glu Val Gln Leu Met Gln Ser
485 490 495
Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys
500 505 510
Gly Ser Gly Tyr Ser Phe Ser Phe His Trp Ile Ala Trp Val Arg Gln
515 520 525
Met Pro Gly Lys Gly Leu Glu Trp Met Gly Ile Ile His Pro Gly Ala
530 535 540
Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser
545 550 555 560
Ala Asp Asn Ser Asn Ser Ala Thr Tyr Leu Gln Trp Ser Ser Leu Lys
565 570 575
Ala Ser Asp Thr Ala Met Tyr Phe Cys Ala Arg Gln Arg Glu Leu Asp
580 585 590
Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
595 600 605
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile
610 615 620
Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys Glu Lys
625 630 635 640
Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser Leu His
645 650 655
Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile Lys Tyr
660 665 670
Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
675 680 685
Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala Glu Asp
690 695 700
Ala Ala Ala Tyr Tyr Cys His Gln Ser Ser Ser Leu Pro Leu Thr Phe
705 710 715 720
Gly Gly Gly Thr Lys Val Glu Ile Lys
725
<210> 75
<211> 2109
<212> DNA
<213> 人工序列
<400> 75
caggtgcagc tggtggagag cggaggtggc gtggtgcagc caggacgaag tctgcgcctg 60
agctgcgccg ccagcggctt caccttcagc gtgtacggca tgaactgggt gcgccaggcc 120
cccggcaagg gcctggagtg ggtggccatc atctggtacg acggcgacaa ccagtactac 180
gccgacagcg tgaagggccg cttcaccatc agccgcgaca acagcaagaa caccctgtac 240
ctgcagatga acggcctgcg cgccgaggac accgccgtgt actactgcgc ccgcgacctg 300
cgcaccggcc ccttcgacta ctggggccag ggcaccctgg tgaccgtgag cagcgcatca 360
acaaagggac caagcgtgtt tccactggcc ccctccagca agagcacctc cggagggaca 420
gccgcgctgg gatgtctggt gaaagactac ttccccgagc ctgtgactgt ctcttggaat 480
agtggcgctc tgacctccgg ggtgcacaca tttccagcag tcctgcagtc ctctggactg 540
tattctctga gtagcgtggt caccgtgccc agctcctctc tgggcactca gacctacatc 600
tgcaatgtca accataagcc tagtaacaca aaagtggata agaaagtcga accaaagagc 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctc cagtcgccgg accgtcagtc 720
ttcctcttcc ctccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 900
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960
tgcaaggtct ccaacaaagg cctcccaagc tccatcgaga aaaccatctc caaagccaaa 1020
gggcagcccc gagaaccaca ggtgtacacc ctgcctccat cccgggatga gctgaccaag 1080
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320
ctctccctgt ctccgggtaa aggaggcagc gggggaagcg gcggcggagg gtctggagga 1380
gggggcagtg aagtccaact gatgcaaagc ggagctgaag ttaagaagcc cggagagtca 1440
ttgaaaataa gttgtaaggg gtccgggtac tccttcagtt tccattggat cgcatgggtg 1500
cgacaaatgc cgggaaaagg actcgagtgg atggggatta tccatcctgg agcctcagac 1560
acccgctatt ctccgagctt tcaaggtcaa gtgacaattt ccgcagataa cagtaattcc 1620
gcgacctatt tgcaatggtc aagtctcaag gccagtgata cggcgatgta cttctgcgcc 1680
agacaacggg aacttgatta cttcgactac tggggacagg ggacccttgt aacagttagc 1740
tccggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctga gatagtgctc 1800
acgcaatcac ccgattttca atctgtcacg cctaaagaga aggtcactat aacctgtaga 1860
gcgagtcagt caataggctc ctcacttcac tggtaccagc aaaaacctga ccaaagcccc 1920
aaattgctca taaagtacgc cagccaatcc ttcagtggag tgccaagcag gttctccggg 1980
tctggctctg gtactgactt cactttgacc attaacagcc tcgaggccga agacgctgca 2040
gcctactatt gtcaccagtc atccagcctt ccgctgactt tcggtggtgg tacaaaggta 2100
gagattaag 2109
<210> 76
<211> 703
<212> PRT
<213> 人工序列
<400> 76
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Val Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Trp Tyr Asp Gly Asp Asn Gln Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly
435 440 445
Gly Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
450 455 460
Val Gln Leu Met Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser
465 470 475 480
Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Phe His Trp
485 490 495
Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly
500 505 510
Ile Ile His Pro Gly Ala Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln
515 520 525
Gly Gln Val Thr Ile Ser Ala Asp Asn Ser Asn Ser Ala Thr Tyr Leu
530 535 540
Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Phe Cys Ala
545 550 555 560
Arg Gln Arg Glu Leu Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
565 570 575
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
580 585 590
Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser
595 600 605
Val Thr Pro Lys Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser
610 615 620
Ile Gly Ser Ser Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro
625 630 635 640
Lys Leu Leu Ile Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser
645 650 655
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
660 665 670
Ser Leu Glu Ala Glu Asp Ala Ala Ala Tyr Tyr Cys His Gln Ser Ser
675 680 685
Ser Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
690 695 700

Claims (13)

1.一种双特异性分子，其包括：
a)特异性结合IL-1R的分子；
b)靶向游离炎症因子的抗体；
其中，所述特异性结合IL-1R的分子为IL-1RA多肽，所述IL-1RA多肽的氨基酸序列如SEQID NO:50所示；
所述游离炎症因子为IL-1β、IL-17或IL-6；
所述IL-1RA多肽与所述靶向炎症因子的抗体通过连接肽连接。
2.权利要求1的双特异性分子，其中，靶向所述游离炎症因子IL-1β的抗体重链可变区序列和轻链可变区序列分别如SEQ ID NO:2和SEQ ID NO:4所示；或者分别如SEQ ID NO:6和SEQ ID NO:8所示。
3.权利要求1的双特异性分子，其中，靶向所述游离炎症因子IL-17的抗体重链可变区序列和轻链可变区序列分别如SEQ ID NO:26和SEQ ID NO:28所示。
4.权利要求1的双特异性分子，其中，靶向所述游离炎症因子IL-6的抗体重链可变区序列
和轻链可变区序列分别如SEQ ID NO:38和SEQ ID NO:40所示。
5.权利要求1-4中任一项的双特异性分子，其中，靶向所述游离炎症因子的抗体为嵌合抗体、人源化抗体、人源抗体或上述这些抗体的重组改变部分。
6.权利要求1的双特异性分子，其中，所述双特异性分子包括靶向游离炎症因子IL-1β的抗体，且所述双特异性分子包含分别具有如下氨基酸序列的重链和轻链：SEQ ID NO:10和SEQ ID NO:4；SEQ ID NO:2和SEQ ID NO:12；SEQ ID NO:14和SEQ ID NO:4；SEQ ID NO:2和SEQ ID NO:16；SEQ ID NO:18和SEQ ID NO:4；SEQ ID NO:2和SEQ ID NO:20；SEQ ID NO:6和SEQ ID NO:22；SEQ ID NO:6和SEQ ID NO:24；SEQ ID NO:62和SEQ ID NO:4；SEQ IDNO:64和SEQ ID NO:4；SEQ ID NO:66和SEQ ID NO:8；SEQ ID NO:6和SEQ ID NO:68；SEQ IDNO:70和SEQ ID NO:4；SEQ ID NO:72和SEQ ID NO:4；SEQ ID NO:74和SEQ ID NO:4；SEQ IDNO:76和SEQ ID NO:4。
7.权利要求1的双特异性分子，其中，所述双特异性分子包括靶向游离炎症因子IL-17的抗体，且所述双特异性分子包含分别具有如下氨基酸序列的重链和轻链：SEQ ID NO:34和SEQ ID NO:28；SEQ ID NO:26和SEQ ID NO:36；SEQ ID NO:30和SEQ ID NO:28；SEQ IDNO:26和SEQ ID NO:32。
8.权利要求1的双特异性分子，其中，所述双特异性分子包括靶向游离炎症因子IL-6的抗体，且所述双特异性分子包含分别具有如下氨基酸序列的重链和轻链：SEQ IDNO:46和SEQ ID NO:40；SEQ ID NO:38和SEQ ID NO:48；SEQ ID NO:38和SEQ ID NO:44；SEQ ID NO:42和SEQ ID NO:40。
9.一种核酸，编码如权利要求1-8中任一项所述的双特异性分子，或其重链或轻链。
10.一种表达载体，其包含如权利要求9所述的核酸。
11.一种宿主细胞，其包含如权利要求10所述的表达载体。
12.一种药物组合物，其包含如权利要求1-8中任一项所述的双特异性分子和药学上可接受的载体或制剂。
13.权利要求1-8中任一项所述的双特异性分子在制备用于治疗炎症性疾病和/或自身免疫性疾病的药物中的用途。
CN202080009752.8A 2019-05-20 2020-05-19 一种双特异性分子及其制备与用途 Active CN113316587B (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201910419818 2019-05-20
CN201910419818X 2019-05-20
PCT/CN2020/091060 WO2020233571A1 (zh) 2019-05-20 2020-05-19 一种双特异性分子及其制备与用途

Publications (2)

Publication Number Publication Date
CN113316587A CN113316587A (zh) 2021-08-27
CN113316587B true CN113316587B (zh) 2024-03-26

Family

ID=73458354

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202080009752.8A Active CN113316587B (zh) 2019-05-20 2020-05-19 一种双特异性分子及其制备与用途

Country Status (4)

Country Link
US (1) US20220233710A1 (zh)
EP (1) EP3974445A4 (zh)
CN (1) CN113316587B (zh)
WO (1) WO2020233571A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK3283110T3 (da) 2015-04-15 2022-05-23 Anaptysbio Inc Antistoffer rettet mod interleukin-36-receptor (il-36r)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004022718A2 (en) * 2002-09-06 2004-03-18 Amgen, Inc. Therapeutic human anti-il-1r1 monoclonal antibody
WO2011084808A2 (en) * 2009-12-21 2011-07-14 Amunix Operating Inc. Bifunctional polypeptide compositions and methods for treatment of metabolic and cardiovascular diseases
WO2016160923A1 (en) * 2015-03-31 2016-10-06 Janssen Biotech, Inc Antigen binding proteins
CN107723310A (zh) * 2017-10-19 2018-02-23 北京睿诚海汇健康科技有限公司 植物作为宿主在表达卡那抗体中的应用
WO2018158741A1 (en) * 2017-03-03 2018-09-07 Novartis Ag Psoriasis disease modification following long-term treatment with an il-17 antagonist
CN109563155A (zh) * 2016-05-27 2019-04-02 北京伟德杰生物科技有限公司 抗体、包含该抗体的组合物和试剂盒及其使用方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2833147A1 (en) * 2011-04-15 2012-10-18 Anita SESHIRE Anti- il-1r1 inhibitors for use in cancer
EP2718457A4 (en) * 2011-06-06 2014-12-24 Immungene Inc GENETICALLY MODIFIED FUSION MOLECULES LIGAND TNFSF-ANTIBODY ELEMENT
WO2014144280A2 (en) 2013-03-15 2014-09-18 Abbvie Inc. DUAL SPECIFIC BINDING PROTEINS DIRECTED AGAINST IL-1β AND / OR IL-17
GB201400997D0 (en) * 2014-01-21 2014-03-05 Vib Vzw Targeting of interleukin-1 and -18 in treatment of septic shock
WO2017210749A1 (en) * 2016-06-10 2017-12-14 Adelaide Research & Innovation Pty Ltd Methods and products for treating autoimmune diseases
KR20200018781A (ko) * 2017-06-19 2020-02-20 스위디쉬 오르펀 바이오비트럼 에이비 (피유비엘) 반감기 연장 폴리펩티드를 갖는 융합 단백질

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004022718A2 (en) * 2002-09-06 2004-03-18 Amgen, Inc. Therapeutic human anti-il-1r1 monoclonal antibody
WO2011084808A2 (en) * 2009-12-21 2011-07-14 Amunix Operating Inc. Bifunctional polypeptide compositions and methods for treatment of metabolic and cardiovascular diseases
WO2016160923A1 (en) * 2015-03-31 2016-10-06 Janssen Biotech, Inc Antigen binding proteins
CN109563155A (zh) * 2016-05-27 2019-04-02 北京伟德杰生物科技有限公司 抗体、包含该抗体的组合物和试剂盒及其使用方法
WO2018158741A1 (en) * 2017-03-03 2018-09-07 Novartis Ag Psoriasis disease modification following long-term treatment with an il-17 antagonist
CN107723310A (zh) * 2017-10-19 2018-02-23 北京睿诚海汇健康科技有限公司 植物作为宿主在表达卡那抗体中的应用

Also Published As

Publication number Publication date
EP3974445A4 (en) 2023-03-22
CN113316587A (zh) 2021-08-27
WO2020233571A1 (zh) 2020-11-26
EP3974445A1 (en) 2022-03-30
US20220233710A1 (en) 2022-07-28

Similar Documents

Publication Publication Date Title
KR102831970B1 (ko) 항-sars-cov-2 스파이크 당단백질 항체 및 항원-결합 단편
US20230340160A1 (en) Bispecific t cell activating antigen binding molecules
CN111954680B (zh) IL2Rβ/共同γ链抗体
CN110719920B (zh) 蛋白质异二聚体及其用途
CN110869389B (zh) 抗ror1抗体及其制备和使用方法
RU2761115C1 (ru) Биспецифические антитела, специфические в отношении костимуляторного tnf-рецептора
CN112225817B (zh) 卷曲螺旋免疫球蛋白融合蛋白及其组合物
AU2021254602A1 (en) Humanized anti-MUC1* antibodies
DK2519543T3 (en) HETERODIMER BINDING PROTEINS AND USE THEREOF
KR102182485B1 (ko) 단백질 약물의 불활성화를 위한 항체 로커
CN106399276B (zh) 治疗性核酸酶组合物和方法
KR20180054877A (ko) 공자극 tnf 수용체에 대해 4가를 갖는 이중특이적 항체
KR20150122203A (ko) T 세포 활성화 이중특이적 항원 결합 분자
KR20150122761A (ko) Ｔ 세포 활성화 항원 결합 분자
CN110234662A (zh) 组织特异性wnt信号增强分子和其用途
KR20180099723A (ko) 항-tl1a/항-tnf-알파 이중특이적 항원 결합 단백질 및 그의 용도
CN113646328B (zh) 一种免疫细胞因子及其制备与用途
KR20200139130A (ko) 유도 및 네비게이션 제어 단백질의 제조 및 사용 방법
KR20110043643A (ko) 인터루킨 6 면역치료제
KR20220154710A (ko) 소형 유도 및 항법 제어(miniGNC) 항체-유사 단백질 및 이의 제조 및 사용 방법
CN113493506A (zh) 新型冠状病毒抗体及其应用
KR20230017815A (ko) 항-sars-cov-2 스파이크 당단백질 항체 및 항원-결합 단편
TW202216743A (zh) Ｉｌ－１０突變蛋白及其融合蛋白
CN113316587B (zh) 一种双特异性分子及其制备与用途
RU2838544C1 (ru) МИНИАТЮРНЫЕ АНТИТЕЛОПОДОБНЫЕ БЕЛКИ УПРАВЛЕНИЯ И НАВИГАЦИОННОГО КОНТРОЛЯ (miniGNC) И СПОСОБЫ ИХ ПОЛУЧЕНИЯ И ПРИМЕНЕНИЕ

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant