CN1765931A

CN1765931A - GLP-1 fusion protein and its preparation method and medicinal uses

Info

Publication number: CN1765931A
Application number: CN 200510017175
Authority: CN
Inventors: 魏洋; 李玉新; 刘霞; 鲍永利; 单保红; 乌垠
Original assignee: Individual
Current assignee: Individual
Priority date: 2005-09-30
Filing date: 2005-09-30
Publication date: 2006-05-03
Anticipated expiration: 2025-09-30
Also published as: CN100445300C

Abstract

The invention provides GLP-1 fusion proteins and process for preparation, wherein these fusion proteins can be used for the treatment of non-insulin dependent diabetes mellitus and obesity.

Description

GLP-1 fusion rotein and preparation method thereof and medicinal use

Technical field

The present invention discloses a kind of GLP-1 fusion rotein and preparation method thereof, relate to the preparation of the fusion rotein of GLP-1 (7-37) and some polypeptide, the present invention also provides the medicinal use of these fusion roteins in disease treatments such as Regular Insulin non-insulin dependent diabetes and obesity, belongs to technical field of biological genetic engineering.

Background technology

The GLP-1 that the present invention relates to (glucagon-like peptide-1, hereinafter to be referred as: GLP-1) mainly by a kind of 37 polypeptide that amino acid is formed of small intestine L-emiocytosis, its activity form is GLP-1 (7-37) OH and GLP-1 (7-36) NH2 (Mojsov S, J ClinInvest.1987 Feb; 79 (2): 616-9).

The GLP-1 analogue is the new class medicine for the treatment of type ii diabetes now.In April, 2005, united States food and drug administration has ratified exenatide, the medicine that can inject, sell with trade(brand)name Byetta, adjuvant therapy medicaments as the type ii diabetes patient, Byetta is the GLP-1 analogue that comes from lizard saliva, is developed by Eli Lilly and Amylin pharmaceuticals.GLP-1 has obvious reduction patient at the blood sugar of using after the meal, can stimulate the production of Regular Insulin, and it can also play certain fat-reducing effect simultaneously, and can not cause hypoglycemia (Drucker DJ, Diabetes.1998 Feb; 47 (2): 159-69.).Recent research shows that also GLP-1 has regeneration (Drucker DJ, Endocrinology.2003Dec to pancreas; 144 (12): 5145-8.).Because the N-of natural GLP-1 holds the 2nd Ala very fast in vivo by two acyltransferase polypeptide peptase IV (DPP-IV) degraded, has limited its clinical application greatly.In order to prolong biological half-life in its body,, must develop long-acting GLP-1 analogue or class jljl with antienzyme degraded so that it better is applied to as medicine is clinical.

Hyperglycemic-glycogenolytic factor is the 29 amino acid whose polypeptide that produced by pancreas A-cell, and it is opposite with insulin action, can increase blood sugar, suppresses the production of Regular Insulin.Studies show that in the type ii diabetes people, the blood hyperglycemic-glycogenolytic factor is obviously higher, use obviously lowering blood glucose (Shah P, J Clin EndocrinolMetab.2000 Nov of hyperglycemic-glycogenolytic factor antagonist or anti-hyperglycemic-glycogenolytic factor antibody; 85 (11): 4053-9; And Johnson DG, Science.1982Feb 26; 215 (4536): 1115-6).Therefore, development hyperglycemic-glycogenolytic factor antagonist has certain prospect (Djuric SW, Curr Opin InvestigDrugs.2002 Nov as the new drug of treatment II paradiabetes; 3 (11): 1617-23).

Summary of the invention

The invention provides a kind of GLP-1 fusion rotein, is any polypeptide receptor and human normal immunoglobulin Fc part, the segmental fusion rotein of immunoglobulin Fc part in GLP-1 and human glucagon receptor or the hyperglycemic-glycogenolytic factor family.The C-terminal of GLP-1 can be directly or the N-terminal by peptide linker and immunoglobulin Fc part or Porcine glucagon family receptors merge.

The invention discloses the preparation method of GLP-1 fusion rotein.

The present invention also provides GLP-1 and hyperglycemic-glycogenolytic factor family receptors or immunoglobulin Fc meromixis joint together, and this joint is made up of several amino acid that can freely stretch, and can make the albumen that is merged folding better.

GLP-1 fusion rotein of the present invention comprises two polypeptide, and wherein, first polypeptide is the GLP-1 compound, and second is the hyperglycemic-glycogenolytic factor family receptors, and the hyperglycemic-glycogenolytic factor family receptors is selected from:

(1) whole glucagon receptor sequence;

(2) glucagon receptor functional zone-1 mainly add that by the glucagon receptor first film outer ring film district of striding at its two ends forms;

(3) functional zone-1 of any polypeptide receptor in the hyperglycemic-glycogenolytic factor family, mainly the first film outer ring by acceptor adds that the film district of striding at its two ends forms;

(4) functional zone-2 of any polypeptide receptor in the hyperglycemic-glycogenolytic factor family, mainly the 2nd film outer ring by acceptor adds that the film district of striding at its two ends forms;

(5) functional zone-3 of any polypeptide receptor in the hyperglycemic-glycogenolytic factor family, mainly the 3rd film outer ring by acceptor adds that the film district of striding at its two ends forms;

(6) GLP-1, GLP-2 or glucose rely on the acceptor that Regular Insulin nutrition polypeptide etc. belongs to the hyperglycemic-glycogenolytic factor family polypeptides.

Wherein the C of first polypeptide end merges with the N end of second polypeptide or is connected by peptide linker.

Peptide linker preferably from:

(1) peptide that has (Gly-Thr-Gly) n, wherein n is 1,2,3,4,5,6;

(2) peptide that has (Gly-Ala-Pro) n, wherein n is 1,2,3,4,5,6;

(3) peptide that has (Gly-Pro-Gly) n, wherein n is 1,2,3,4,5,6;

(4) peptide that has (Gly-Gly-Gly-Gly-Ser) n.Wherein n is 1,2,3,4,5,6.

Fusion rotein of the present invention can also be the fusion of GLP-1 compound and human normal immunoglobulin Fc section, and wherein, human normal immunoglobulin Fc section is selected from:

(1) the Fc part of human normal immunoglobulin;

(2) analogue of the Fc of human normal immunoglobulin part;

(3) fragment of the Fc of human normal immunoglobulin part.

The fusion of above-mentioned two polypeptide can merge with the N end of second polypeptide for the C end of first polypeptide or be connected by peptide linker.Peptide linker preferably from:

(1) peptide that has (Gly-Thr-Gly) n, wherein n is 1,2,3,4,5,6;

(2) peptide that has (Gly-Ala-Pro) n, wherein n is 1,2,3,4,5,6;

(3) peptide that has (Gly-Pro-Gly) n, wherein n is 1,2,3,4,5,6;

(4) peptide of n Gly-Gly-Gly-Gly-Ser).Wherein n is 1,2,3,4,5,6.

Fusion rotein of the present invention also can be that three polypeptide merge, wherein, first polypeptide is the GLP-1 compound, the Fc section that second polypeptide is human normal immunoglobulin or the fragment of Fc section, and the 3rd polypeptide is the acceptor of any polypeptide in human glucagon receptor or the hyperglycemic-glycogenolytic factor family.

Wherein three polypeptide directly link to each other or connect by intermediate head, intermediate head preferably from:

(1) peptide that has (Gly-Thr-Gly) n, wherein n is 1,2,3,4,5,6;

(2) peptide that has (Gly-Ala-Pro) n, wherein n is 1,2,3,4,5,6;

(3) peptide that has (Gly-Pro-Gly) n, wherein n is 1,2,3,4,5,6;

(4) peptide that has (Gly-Gly-Gly-Gly-Ser) n.Wherein n is 1,2,3,4,5,6.

As the GLP-1 of a fusion rotein part general preferred have be no more than 6 and be different from GLP-1 (7-37) OH, the corresponding amino acid whose amino acid among GLP-1 (7-36) OH or the Exendin-4.GLP-1 compound even more preferably have and be no more than 5 and be different from GLP-1 (7-37) OH, the corresponding amino acid whose amino acid among GLP-1 (7-36) OH or the Exendin-4.The GLP-1 compound most preferably has and is no more than 4,3 or 2 and is different from GLP-1 (7-37) OH, the corresponding amino acid whose amino acid among GLP-1 (7-36) OH or the Exendin-4.

GLP-1 fusion rotein of the present invention can obtain by following preparation method: gene recombination technology or solid phase protein synthesis technology.

The concrete technical solution of recombination method production fusion rotein of the present invention is as follows:

One, makes up the recombinant vectors of code book invention fusion rotein

(1) angling of GLP-1 got

According to disclosed GLP-1 sequences Design PCR primer, with the cDNA of expressing human GLP-1, as pancreas, small intestine, cerebral tissue cDNA are template, obtain GLP-1 cDNA sequence through pcr amplification.

(2) glucagon receptor and angling of other acceptor of family thereof are got

The glucagon receptor part can human liver tissue cDNA be a template in the fusion rotein, uses the primer of corresponding acceptor, obtains through pcr amplification, is cloned into TOPO TA carrier (Invitrogen) then, and the carrier of reorganization is cut and the sequential analysis evaluation through the EcoRI enzyme.The plasmid that is obtained is called TOPO TA-glucagon receptor at this.

Glucagon receptor N-terminal membrane ectodomain; Functional zone-1; Functional zone-2; Functional zone-3 fragment can above-mentioned TOPO TA-glucagon receptor be a template, with corresponding primer, obtains through pcr amplification.

Other acceptor of hyperglycemic-glycogenolytic factor family can angle with the method identical with glucagon receptor and get.

Have no progeny having obtained the said gene sheet, available ligase enzyme connects corresponding gene, and also available overlapping PCR method merges it, is cloned into expression vector then.

(3) angling of human IgG1 Fc section got

Being template with people's tissue cDNA of expressing IgG angles the CH2 that gets coding human IgG1 hypotype and the cDNA sequence of CH3 functional zone through pcr amplification, it is cloned into pV05 carrier (Fig. 6), the plasmid called after pV05-human IgG1 Fc that is obtained.

(4) structure of recombinant expression vector

Make up the gene of encoding fusion protein by the DNA of the DNA of connection coding GLP-1 in the frame and encode immunoglobulin Fc part or hyperglycemic-glycogenolytic factor and analogue acceptor thereof.Also can be by the gene of connection coding GLP-1 gene in the gene frame of coding joint peptide with coding immunoglobulin Fc part or hyperglycemic-glycogenolytic factor and analogue acceptor thereof.

Encoding wild type GLP-1, hyperglycemic-glycogenolytic factor and analogue acceptor thereof, Fc polypeptide and segmental DNA can be before being connected or suddenling change in the scope of the cDNA of the whole fusion rotein of coding.Multiple induced-mutation technique is well known in the art.For example, utilize the overlapping extension of chain to be used for changing the mutagenesis PCR method of particular bases sudden change of the specific amino acids sequence of corresponding protein with preparation.

When with the mammalian cell expression fusion rotein, signal peptide must be arranged, so that the fusion rotein of expressing can be secreted into endochylema, signal peptide is excised automatically.The signal peptide of hyperglycemic-glycogenolytic factor also can use other signal peptide before the present invention used, as: the signal peptide of preceding parathryoid hormone (Wiren, KM etc.The J of Bio.Chem.263 (36): 19771-19777 (1988), or the signal peptide of human IgG1 Fc.

When with the bacterial expression fusion rotein, can adopt bacterium expressing fusion protein method, add proteolytic enzyme point of contact and HA or 6HIS label at the N end and be used for adsorption and purification, the fusion rotein of expression obtains containing the fusion rotein in correct excision site after the proteolytic enzyme enzyme is cut.Also can use up-to-date IMPACT bacterial expression system (New England, BioLabs Inc.).This IMPACT albumen merges and purification system is to utilize self lytic activity of derivable engineered protein shearing elements to carry out protein purification and processing.Come purifying protein by pH and temperature-induced cracking: use the pTWIN carrier, this intein label is to merge at the N-of target protein end.Be released by pH and thermoinducible cracking after this target protein.

In case produced the gene of the complete fusion rotein of encoding, it can be cloned into suitable expression.

Two, express the general method of fusion rotein of the present invention

With expression vector transfection described herein or transformed host cell, be used to produce fusion rotein, this host cell can be eucaryon or prokaryotic organism host cell.Technology with recombinant DNA carrier conversion or transfectional cell is a technology well known in the art.

Three, reclaim the also protein of purification of Recombinant generation

Can be by coming the fusion rotein of purifying expression with corresponding column chromatography at the sequence label of N-end or the adding of C-end or the characteristic of fusion rotein.

Four, the activity of fusion rotein detects

(1) fusion rotein is external in conjunction with determination of activity

Commercial GLP-1 (7-36) with the 125I mark combines the GLP-1 acceptor with fusion rotein competition of the present invention, and the result shows that fusion rotein of the present invention is active in commercial people GLP-1 (7-36) with combining of GLP-1 acceptor.

(2) fusion rotein is in external influence to the cAMP level

The recombinant vectors transfection that will contain the GLP-1 receptor cdna is measured cAMP (Wei and Mojsov by the described method of document to Chinese hamster ovary celI after 48 hours, 1996), the result shows that fusion rotein of the present invention is basic identical at external influence and commercial people GLP-1 (7-36) to the cAMP level.

(3) pharmacokinetics of fusion rotein detects

Give injection fusion rotein (50nM) in the C57BL/6 mouse vein, respectively at injection back 0min, 1hr, 6hr, 12hr, 24hr, 36hr, 48hr takes a blood sample in the tail vein behind 60hr and the 72hr.4 ℃ of centrifugal separation plasmas detect the fusion rotein level with the ELISA method.The result shows that the biological half-life of fusion rotein of the present invention, more simple GLP-1 obviously prolonged.

(4) fusion rotein is to the influence of the anti-sugared ability of mouse

Give fusion rotein (the 4 μ g/kg of mouse (C57BL/6) the subcutaneous injection various dose that spend the night (16-18h) go on a hunger strike, 16 μ g/kg, 80 μ g/kg and 1mg/kg) or physiological saline, behind injection 30min and the 24h, press 1.5mg/g body weight abdominal injection glucose, and respectively at injection back 0,10,20,30,60,90 and 120min after take blood sample from the tail point.Detect glucose level in the blood with the glucose table by the glucolase method.The result shows and to give that the anti-sugared ability of mouse obviously improves behind the fusion rotein of the present invention, give 0.07nmol/kg fusion rotein of the present invention and promptly have the obvious functions of blood sugar effect, and the concentration of its function of polysaccharide and fusion rotein is proportionate, when fusion rotein was increased to 18nmol/kg, it is more obvious that its function of blood sugar reduction becomes.

To sum up, the interior biologic activity detected result of external and body shows that the fusion rotein that the present invention prepares not only has the normal biologic activity of GLP-1, and its biological half-life, more independent GLP-1 polypeptide obviously prolonged.

Fusion rotein pharmaceutical composition and purposes

Fusion rotein of the present invention can be used for treating katabolism change after Regular Insulin non-insulin dependent diabetes, insulin-dependent diabetes mellitus, palsy, myocardial infarction, obesity, the operation, functional dyspepsia and irritable bowel syndrome.Also comprise the patient that need utilize the GLP-1 compound to carry out preventative processing, as have the patient that Regular Insulin non-insulin dependent diabetes danger takes place: unusual or unusual experimenter, the body weight of fasting glucose of glucose tolerance exceeds experimenter with respect to the normal type 25% of patient's height and physique, carried out the experimenter of part pancreas resection operation, suffers from the experimenter of gestational diabetes and suffer from urgency or the experimenter of chronic pancreatitis.Fusion rotein of the present invention had both kept the biologic activity of GLP-1, had prolonged GLP-1 biological half-life in vivo again simultaneously, and therefore fusion rotein of the present invention can be used for above treatment of diseases.

The present invention also provides a kind of pharmaceutical composition, and it comprises above-mentioned fusion rotein or the pharmaceutically acceptable carrier or the thinner of significant quantity.

Activeconstituents dosage in the present composition can be different, but the amount of activeconstituents must can obtain suitable formulation.Selected dosage changes according to required result of treatment, route of administration and treatment cycle.In general, the significant quantity of activeconstituents of the present invention is 1 * 10 ^-7-200mg/kg/ days, 1 * 10 ^-4-100mg/kg/ days, can single dose administration or be divided into multiple dose administration.

Fusion rotein of the present invention can oral administration, parenteral (as muscle, intraperitoneal, intravenously, subcutaneous injection or implantation), nasal cavity, vagina, rectum, the hypogloeeis or partial route of administration are carried out administration, and can be prepared the formulation that is suitable for each route of administration to provide with pharmaceutically acceptable carrier.

Oral solid dosage comprises capsule, tablet, pill, pulvis and granule.In these solid dosages, active compound is mixed with at least a pharmaceutically acceptable inert support, this carrier is sucrose, lactose or starch for example.These formulations can normally be used other material that also can comprise except that inert diluent, and lubricant for example is as Magnesium Stearate.In capsule, tablet and pill, these formulations also can comprise buffer reagent.Tablet and pill can prepare with casing in addition.

That oral liquid dosage form comprises is pharmaceutically acceptable, contain the normally used inert diluent in this area, as emulsion, solution, suspension, the syrup of water.Except these inert diluents, composition also can comprise auxiliary, for example wetting agent, emulsifying agent, suspension agent, sweeting agent, seasonings and flavouring agent.

The preparation that the present invention is used for parenterai administration comprises aseptic aqueous solution or non-aqueous solution, suspension or emulsion.Non-aqueous solvent or vehicle, for example propylene glycol, polyoxyethylene glycol, vegetables oil (as sweet oil and Semen Maydis oil), gelatin, injectable organic ester (as ethyl oleate).These formulations also can comprise the auxiliary such as sanitas, wetting agent, emulsifying agent and dispersion agent.Can sterilize by the following method, for example retain strainer and filter, in composition, add disinfectant, irradiation composition or heating combination through bacterium.Also they can be made the form of aseptic solid composite, immediately it is dissolved in sterilized water or other the injectable sterile media before the use.

The preferred suppository of the composition of rectum or vagina administration, except active substance, it can comprise vehicle, for example theobroma oil or suppository wax.

Also available standard excipients well known in the art prepares the composition of nasal cavity or sublingual administration.In addition, the present composition can be with the form administration of sustained-release composition.

Positively effect of the present invention is: GLP-1 can keep its natural function in the fusion rotein, hyperglycemic-glycogenolytic factor family receptors part and human IgG Fc fragment part then can prolong the GLP-1 transformation period, and the hyperglycemic-glycogenolytic factor family receptors have in and the effect of hyperglycemic-glycogenolytic factor, can play dual hypoglycemic effect; Human IgG Fc fragment part then helps the purifying of fusion rotein.

Partly to prolong the reason of GLP-1 transformation period as follows for the hyperglycemic-glycogenolytic factor family receptors among the present invention:

The the 1st and the 3rd film outer ring of glucagon receptor can combine with the N-end of hyperglycemic-glycogenolytic factor.The N-end of GLP-1 and hyperglycemic-glycogenolytic factor are much at one; therefore GLP-1 can with faint combination of glucagon receptor (or acceptor of other polypeptide of hyperglycemic-glycogenolytic factor family); this faint combination can protect GLP-1 to exempt from the degraded of DPPIV to a certain extent, so can prolong the transformation period of GLP-1.Equally; when with GLP-1 and GLP-1 acceptor or when partly functional zone merge; GLP-1 will with the partly faint combination of the acceptor that is attached thereto; with protection GLP-1; when fusion rotein meets natural receptor; its bonding force is stronger than the acceptor portion of fusion rotein, so GLP-1 tends to combine with natural receptor in the fusion rotein, brings into play its biological effect.

Except as otherwise noted, the implication of all technology used herein and scientific terminology and those skilled in the art's common sense is identical.

Description of drawings

Fig. 1 has shown fusion rotein PPS 601 immunoblotting results

Fig. 2 a has shown the GLP-1 receptor sequence

Fig. 2 b shows the result that combines of fusion rotein PPS601 and people GLP-1 (7-37) acceptor

Fig. 3 has shown the influence of fusion rotein PPS601 to the cAMP level

Fig. 4 has shown the interior pharmacokinetics result of the body of fusion rotein PPS601

Fig. 5 has shown the influence of fusion rotein PPS601 to the anti-sugared ability of mouse

Fig. 6 has shown pV05 carrier figure

Fig. 7 has shown PPS601 recombinant vectors figure

Embodiment:

The following example is in order to help to describe how to implement various embodiments of the present invention.These embodiment illustrate for example, rather than limit scope of the present invention by any way.

Embodiment 1

The structure of fusion rotein carrier

The cDNA that GLP-1 part can any expressing human GLP-1 in the fusion rotein, as pancreas, small intestine, cerebral tissue cDNA are template, obtain through pcr amplification.Mouse has identical GLP-1 aminoacid sequence with the people, so can replace people cDNA.

Can comprise the DNA of the method preparation coding GLP-1 of the present invention of above-mentioned cloning process and chemical synthesising DNA by various method.

The glucagon receptor part can human liver tissue cDNA be a template in the fusion rotein, and primer is 5 '-ATGCCCCCCTGCCAGCCACAG-3 ' and 5 '-TCAGAAGGGGCTCTCAGCCAATC-3 ', obtains through pcr amplification.The glucagon receptor that is increased is 1431bp, and it is cloned into TOPO TA carrier (Invitrogen), and the carrier of reorganization is cut and the sequential analysis evaluation through the EcoRI enzyme.The plasmid that is obtained is called TOPO TA-glucagon receptor at this.

Glucagon receptor N-terminal membrane ectodomain; Functional zone-1; Functional zone-2; Functional zone-3 fragment can above-mentioned TOPO TA-glucagon receptor be a template, with corresponding primer, obtains through pcr amplification.Have no progeny having obtained the said gene sheet, can corresponding gene be connected the preparation fusion rotein through ligase, also available overlapping PCR method merges it.Be cloned into expression vector then.

The GLP-1 acceptor can human liver tissue cDNA be a template in the fusion rotein, uses primer 5 '-ATGGCCGGCGCCCCCGGC-3 ' and 5 '-TCAGCTGTAGGAGGCCTGGC-3 ', obtains through pcr amplification.The GLP-1 acceptor that is increased is 1392bp, and it is cloned into TOPO TA carrier (Invitrogen), and the carrier of reorganization is cut and the sequential analysis evaluation through the EcoRI enzyme.The plasmid that is obtained is called TOPO TA-GLP-1 acceptor at this.

GLP-1 acceptor N-terminal membrane ectodomain; Functional zone-1; Functional zone-2; Functional zone-3 fragment can above-mentioned TOPO TA-GLP-1 acceptor be a template, with corresponding primer, obtains through pcr amplification.Have no progeny having obtained the said gene sheet, can corresponding gene be connected the preparation fusion rotein through ligase, also available overlapping PCR method merges it.Be cloned into expression vector then.

The GLP-2 acceptor can human liver tissue cDNA be a template in the fusion rotein, uses primer 5 '-ATGAAGCTGGGATCGAGCAG-3 ' and 5 '-CTAGATCTCACTCTCTTCCAG-3 ', obtains through pcr amplification.The GLP-2 acceptor that is increased is 1162bp, and it is cloned into TOPO TA carrier (Invitrogen), and the carrier of reorganization is cut and the sequential analysis evaluation through the EcoRI enzyme.The plasmid that is obtained is called TOPO TA-GLP-2 acceptor at this.

GLP-2 acceptor N-terminal membrane ectodomain; Functional zone-1; Functional zone-2; Functional zone-3 fragment can above-mentioned TOPO TA-GLP-2 acceptor be a template, with corresponding primer, obtains through pcr amplification.Have no progeny having obtained the said gene sheet, can corresponding gene be connected the preparation fusion rotein through ligase, also available overlapping PCR method merges it.Be cloned into expression vector then.

The Fc section of immunoglobulin G while 1 can use and anyly have people's tissue cDNA of expression to obtain through pcr amplification in the fusion rotein.(GIBCO angles in BRL) and gets people the encode CH2 of IgG1 hypotype and the cDNA sequence of CH3 functional zone from the human cDNA library.The primer is: 5 '-AAAAGGCCCGGGCGACAAAACTCACACATGC-3 ' (containing the SrfI restriction enzyme site) and 5 '-ATTTCGCCGGCGTTATTTACCCGGAGACAGGG-3 ' (containing the NotI restriction enzyme site) this to primer be used to the to increase 214-467bp zone of IgG1 heavy chain coding region, it comprises hinge area, CH2 and CH3 functional zone (Strausberg, R.L.etc.Proc.Natl.Acad.Sci.U.S.A.99 (26), 16899-16903 (2002)).The Fc of the immunoglobulin G while 1 that obtains is 759bp, contain intermediate head GGCCCGGGC (SrfI restriction enzyme site) at its 5 '-end, contain TAA terminator codon and NotI restriction enzyme site at its 3 '-end, it is cloned into pV05 carrier (Fig. 6), the plasmid called after pV05-people immune protein G1Fc that is obtained.

When with the bacterial expression fusion rotein, can adopt bacterium expressing fusion protein method, add proteolytic enzyme point of contact and HA or 6HIS TAG at the N end and be used for adsorption and purification, the fusion rotein of expression obtains containing the fusion rotein in correct excision site after the proteolytic enzyme enzyme is cut.Also can use up-to-date IMPACT bacterial expression system (New England, BioLabs Inc.).This IMPACT albumen merges and purification system is to utilize self lytic activity of derivable engineered protein shearing elements to carry out protein purification and processing.Come purifying protein by pH and temperature-induced cracking: use the pTWIN carrier, this intein label is to merge at the N-of target protein end.Be released by pH and thermoinducible cracking after this target protein.

Embodiment 1a

The structure of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-glucagon receptor N-terminal membrane ectodomain-people's immune protein G1Fc recombinant vectors:

With the mouse brain tissue cDNA is template, uses following primer:

(a)5’-CCCAAGCTT ATGAAGACCATTTACTTTGT-3’

(b)5’-GGTCCCTTCAGCATGCTGCCAGCTGCCTTGCAC-3’

(c)5’-CATGCTGAAGGGACCTTTAC-3’

(d)5’-AAAAGGCGCGCCTTCCTCGGCCTTTCACCAGCC-3’

Pcr amplification can obtain Proglucagon signal peptide and GLP-1 encoding sequence respectively.3 ' end of institute's picked up signal peptide inserts 15bp GLP-15 ' terminal sequence through primer, with primer (a), (d) through overlapping PCR signal peptide and GLP-1 is merged again.At primer (b) and (c) Ala is become Gly (GAA becomes GCT), ' and 3 ' end inserts HindIII respectively and the AscI restriction enzyme site is used for the clone for the fragment 5 that is obtained.

With TOPO TA-glucagon receptor is template, uses following primer:

(e)5’-AAGGCGCGCCTGCTCAGGTGATGGACTTC-3’

(f)5’-AAAAGCCCGGGCCCTGGAAGCTGCTGTACATC-3’

Obtain glucagon receptor N-terminal membrane ectodomain through pcr amplification, its 5 '-end contains GGCGCGCCT (AscI restriction enzyme site), and 3 '-end contains GCCCGGGCC (SrfI restriction enzyme site).

After obtaining above-mentioned two fragments, it can be cloned among the Fc of the carrier pV05-people immune protein G1 that HindIII and SrfI enzyme cut, be transformed into HB10D competent cell (invitrogen) then.Recombinant plasmid is through HindIII and the NotI enzyme is cut and sequential analysis is identified entirely true.

The fusion sequence of expressing is [serial ID NO:35]: HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRG-GAP-AQVMDFLFEKWKLYGDQCHH NLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCG PDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQ-GPG-DKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSYLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Embodiment 1b

The structure of the recombinant vectors of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-glucagon receptor functional zone-1-intermediate head-people's immune protein G1Fc

Signal peptide-(the 2nd G replaces A) pulsating preparation of GLP-1 is identical with method 1a.

Glucagon receptor functional zone-1 can use following primer to obtain through pcr amplification:

Amplification glucagon receptor functional zone-1 primer is:

5 '-CCGGCGCGCCTGTCATTGATGGGCTGCTCAG-3 ' (containing the AscI restriction enzyme site) and 5 '-AAAAGCCCGGGCCAGCCACCGCTCCATCACT-3 ' (containing the SrfI restriction enzyme site).

The fragment that above-mentioned PCR is obtained is cut rear clone with HindIII and SrfI enzyme and is gone among the Fc of the carrier pV05-immunoglobulin G while 1 that HindIII and SrfI enzyme cut.The insertion sequence of recombinant plasmid identifies that through nucleotide sequencing its sequence is entirely true.

Embodiment 1c

The structure of the recombinant vectors of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-glucagon receptor functional zone-3-intermediate head-people's immune protein G1Fc

Glucagon receptor functional zone-3 can use following primer to obtain through pcr amplification:

Amplification glucagon receptor functional zone-3 primer is:

5 '-CCGGCGCGCCTGACGAGCACGCCCAGGGC-3 ' (containing the AscI restriction enzyme site)

5 '-AAAAGCCCGGGCCGAGGTCGAAGAAGAGCTT-3 ' (containing the SrfI restriction enzyme site)

Embodiment 1d

The structure of the recombinant vectors of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-glucagon receptor functional zone-1-intermediate head-glucagon receptor functional zone-3-intermediate head-people's immune protein G1Fc:

Glucagon receptor functional zone-1 and functional zone-3 can use following primer to obtain respectively through pcr amplification:

Amplification glucagon receptor functional zone-1 primer is:

5 '-CCGGCGCGCCTGTC ATT GAT GGG CTG CTC AG-3 ' (containing the AscI restriction enzyme site) and 5 ' ACTTCCACCTCCGCCAGCCACCGCTCCATCACT-3 ' (containing the ACTTCCACCTCCGCC intermediate head).

Amplification glucagon receptor functional zone-3 primer is:

5 '-GGCGGAGGTGGAAGTGACGAGCACGCCCAGGGC-3 ' and 5 '-AAAAGCCCGGGCCGAGGTCGAAGAAGAGCTT-3 ' (containing the SrfI restriction enzyme site)

Two fragments that above-mentioned PCR is obtained merge through overlapping PCR, cut rear clone with HindIII and SrfI enzyme and go among the Fc of the carrier pV05-immunoglobulin G while 1 that HindIII and SrfI enzyme cut, the insertion sequence of recombinant plasmid identifies that through nucleotide sequencing its sequence is entirely true.

The fusion rotein sequence of expressing is [serial ID NO:36]:

HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRG-GAP-VIDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-GGGS-DEHAQGTLRSAKLFFDL-GPG-DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Embodiment 1e

The structure of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-people's immune protein G1Fc:

Signal peptide-(G8 replaces A) pulsating preparation of GLP-1 is identical with embodiment 1a.Just replace AscI with SrfI in the primer (d).After the acquisition it is cloned among the Fc of the carrier pV05-people immune protein G1 that HindIII and SrfI enzyme cut.The insertion sequence of recombinant plasmid identifies that through nucleotide sequencing its sequence is entirely true.

The fusion rotein sequence of expressing is [serial ID NO:37]:

HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRG-GAP-DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Embodiment 1f

The structure of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-GLP-1 acceptor-immunoglobulin G while 1Fc recombinant vectors

With the mouse brain tissue cDNA is template, uses following primer:

(a)5’-CCCAAGCTT ATGAAGACCATTTACTTTGT-3’

(b)5’-GGTCCCTTCAGCATGCTGCCAGCTGCCTTGCAC-3’

(c)5’-CATGCTGAAGGGACCTTTAC-3’

(d)5’-AAAAGGCGCGCCTTCCTCGGCCTTTCACCAGCC-3’

Pcr amplification can obtain Proglucagon signal peptide and GLP-1 encoding sequence respectively.3 ' end of institute's picked up signal peptide inserts 15bp GLP-15 ' terminal sequence through primer, with primer (a), (d) through overlapping PCR signal peptide and GLP-1 is merged again.At primer (b) and (c) Ala is become Gly (GAA becomes GCT), ' and 3 ' end inserts HindIII respectively and the AscI restriction enzyme site is used for the clone for the fragment 5 that is obtained.With TOPO TA-GLP-1 acceptor is template, uses following primer:

(e)5’-AAGGCGCGCCTCGCCCCCAGGGTGCCAC-3’

(f)5’-AAAAGCCCGGGCCGCTGCAGGAGGCCTG-3’

Obtain the GLP-1 acceptor through pcr amplification, its 5 '-end contains GGCGCGCCT (AscI restriction enzyme site), and 3 '-end contains GCCCGGGCC (SrfI restriction enzyme site).

After obtaining above-mentioned two fragments, it can be cloned among the Fc of the carrier pV05-people immune protein G1 that HindIII and SrfI enzyme cut, be transformed into HB10D competent cell (invitrogen) then.Recombinant plasmid is through HindIII and the NotI enzyme is cut and sequential analysis identifies that its sequence is entirely true.

Embodiment 1g

The structure of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-GLP-1 acceptor N-terminal membrane ectodomain-immunoglobulin G while 1Fc recombinant vectors

With the mouse brain tissue cDNA is template, uses following primer:

(a)5’-CCCAAGCTT ATGAAGACCATTTACTTTGT-3’

(b)5’-GGTCCCTTCAGCATGCTGCCAGCTGCCTTGCAC-3’

(c)5’-CATGCTGAAGGGACCTTTAC-3’

(d)5’-AAAAGGCGCGCCTTCCTCGGCCTTTCACCAGCC-3’

With TOPO TA-GLP-1 acceptor is template, uses following primer:

(e)5’-AAGGCGCGCCTCGCCCCCAGGGTGCCAC-3’

(f)5’-AAAAGCCCGGGCCGTAGAGGAACAGGAGCTG-3’

Obtain GLP-1 acceptor N-terminal membrane ectodomain through pcr amplification, its 5 '-end contains GGCGCGCCT (AscI restriction enzyme site), and 3 '-end contains GCCCGGGCC (SrfI restriction enzyme site).After obtaining above-mentioned two fragments, it can be cloned among the Fc of the carrier pV05-people immune protein G1 that HindIII and SrfI enzyme cut, be transformed into HB10D competent cell (invitrogen) then.Recombinant plasmid is through HindIII and the NotI enzyme is cut and sequential analysis identifies that its sequence is entirely true.

Embodiment 1h

The structure of the recombinant vectors of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-GLP-1 receptor functional domain-1-intermediate head-immunoglobulin G while 1Fc

GLP-1 receptor functional domain-1 can use following primer to obtain through pcr amplification:

Amplification GLP-1 receptor functional domain-1 primer is:

5 '-CCGGCGCGCCTAACTACATCCACCTGAAC-3 ' (containing the AscI restriction enzyme site) and 5 '-AAAAGCCCGGGCCCAGGTACACGCCCTCCAC-3 ' (containing the SrfI restriction enzyme site).

The fragment that above-mentioned PCR is obtained is cut rear clone with HindIII and SrfI enzyme and is gone among the Fc of the carrier pV05-immunoglobulin G while 1 that HindIII and SrfI enzyme cut, and the insertion sequence of recombinant plasmid identifies that through nucleotide sequencing its sequence is entirely true.

Embodiment 1i

The structure of the recombinant vectors of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-GLP-1 receptor functional domain-2-intermediate head immunoglobulin G while 1Fc

Signal peptide-(the 2nd G replaces A) pulsating preparation of GLP-1 is identical with method 1a.GLP-1 receptor functional domain-2 can use following primer to obtain through pcr amplification:

Amplification GLP-1 receptor functional domain-2 primer is:

5 '-CCGGCGCGCCTTTCAGGCTCTACGTGAGC-3 ' (containing the AscI restriction enzyme site) and 5 '-AAAAGCCCGGGCCGCAGATGACCCGAACAAAG-3 ' (containing the SrfI restriction enzyme site).

The fragment that above-mentioned PCR is obtained is cut rear clone through HindIII and SrfI enzyme and is gone among the Fc of the carrier pV05-immunoglobulin G while 1 that HindIII and SrfI enzyme cut.The insertion sequence of recombinant plasmid identifies that through nucleotide sequencing its sequence is entirely true.

Embodiment 1j

The structure of the recombinant vectors of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-GLP-1 receptor functional domain-3-intermediate head-immunoglobulin G while 1Fc

Signal peptide-(the 2nd G replaces A) pulsating preparation of GLP-1 is identical with method 1a.GLP-1 receptor functional domain-3 can use following primer to obtain through pcr amplification:

Amplification GLP-1 receptor functional domain-3 primer is:

5 '-CCGGCGCGCCITCCACGCTGACACTCATC-3 ' (containing the AscI restriction enzyme site) and 5 '-AAAAGCCCGGGCCCTCATTGTTGACAAAGC-3 ' (containing the SrfI restriction enzyme site)

Embodiment 1k

The structure of the recombinant vectors of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-GLP-1 receptor functional domain-1-intermediate head-GLP-1 receptor functional domain-3-intermediate head-immunoglobulin G while 1Fc

GLP-1 receptor functional domain-1 and functional zone-3 can use following primer to obtain respectively through pcr amplification:

Amplification GLP-1 receptor functional domain-1 primer is:

5 '-CCGGCGCGCCTAACTACATCCACCTGAAC-3 ' (containing the AscI restriction enzyme site) and 5 ' ACTTCCACCTCCGCCCAGGTACACGCCCTCCAC-3 ' (containing the ACTTCCACCTCCGCC intermediate head).

Amplification GLP-1 receptor functional domain-3 primer is:

5 '-GGCGGAGGTGGAAGTTCCACGCTGACACTCATC-3 ' and 5 '-AAAAGCCCGGGCCCTCATTGTTGACAAAGC-3 ' (containing the SrfI restriction enzyme site)

Two fragments that above-mentioned PCR is obtained merge through overlapping PCR, cut rear clone with HindIII and SrfI enzyme and go among the Fc of the carrier pV05-immunoglobulin G while 1 that HindIII and SrfI enzyme cut.The insertion sequence of recombinant plasmid identifies that through nucleotide sequencing its sequence is entirely true.

Embodiment 2

Expression of Fusion Protein

Expression of Fusion Protein in the constructed recombinant vectors can adopt transient transfection CHO method among the embodiment 1.Inoculation Chinese hamster ovary celI 10 in the 10cm culture dish ⁶Individual, cultivate and carry out transfection after 24 hours.With lipofectamine (Invitrogen), OptiMEM and plasmid mixed after; room temperature kept 30 minutes; join then in the washed Chinese hamster ovary celI of serum-free OptiMEM; after the co-cultivation 5 hours; add CHO-S-SFMII media (Gibco cat#31033-020)+1X glutaminate (Gibco cat#25030-081)+10mM Na butyrates (Sigma cat#B5887); cultivated 48 hours in the 37 degree incubators, collect the supernatant liquor that contains expressing protein.

Embodiment 3

The purifying of fusion rotein

The above-mentioned CHO supernatant liquor that contains expressing protein, after the 10K filtering membrane concentrates 10 times, use the Protein G post to remove to catch the fusion rotein that contains Fc, with 50mM citric acid (pH 3.3) wash-out, collect eluate (0.5ml), add among the 100 μ l 1M Tris pH 8.0 and acidity.After OD280nm measures protein content, merge all protein-contg collection tubes, dialyse 2 times in PBS (pH7.4) through the 10K dialysis membrane.

Embodiment 4

The immunoblotting of fusion rotein is identified

Purified material with PPS601 and serum sample under the no inductor inductive condition of PBS dilution that contains 1% SDS and 2mg tetrabromophenol sulfonphthalein.After boiling sex change, get 20 μ l samples and add on the SDS-PAGE glue, behind the electrophoresis, albumen is gone on the nitrocellulose filter.Film is sealed 2hr with 5% skim-milk room temperature, (Sigma USA), uses the luminous colour developing of ECL test kit (Amersham Pharmacia Biotech to the goat anti-human igg of adding HRP mark then, USA), result's fusion rotein of the present invention has as shown in Figure 1 obtained expressing preferably.

Embodiment 5

Fusion rotein external in conjunction with determination of activity

Use pcr amplification obtain the GLP-1 receptor cdna (Fig. 2 a), with it be cloned into pcDNA3.1 (Invitrogen, USA).The transfection of GLP-1 receptor cdna is at war with in conjunction with test (Wei and Mojsov, 1996) by method shown in the document after 48 hours to Chinese hamster ovary celI.With Chinese hamster ovary celI with ¹²⁵I-GLP-1 (7-36) (USA) (USA) or under the GLP-1 fusion rotein situation about existing, hatched 15-18 hour for 4 ℃ at the little peptide of the hGLP-1 that increases concentration (pM-uM) gradually (7-37) for 2200Ci/mmol, New England Nuclear by anaSPEC.Be reflected at and contain 20mMHEPES, pH7.4 carries out in Hank ' the s balanced salt solution of 0.5%BSA and 0.1mM phenylmethylsulfonyl-fluoride (PMSF).After hatching cell is washed twice with ice-cold PBS, use the 1NNaOH cracking, detect radioactivity with the γ calculating instrument, result's fusion rotein of the present invention shown in Fig. 2 b is active in commercial people GLP-1 (7-36) with combining of GLP-1 acceptor.

Embodiment 6

Fusion rotein is in external influence to the cAMP level

The recombinant vectors transfection that will contain the GLP-1 receptor cdna is measured cAMP (Wei and Mojsov, 1996) by the described method of document to Chinese hamster ovary celI after 48 hours.Cell was cultivated 24 hours on 24 orifice plates by renewed vaccination, used damping fluid (Macy ' s 5A pH 7.4,20mM HEPES, 0.5% BSA, 0.5mM IBMX) to hatch then.This cell without any little peptide or contain the hGLP-1 of different concns or the condition of GLP-1 fusion rotein (pM is to μ M) under, cultivated 45 minutes for 37 ℃.Each the experiment in all with forskolin (10 μ M, Sigma, USA) positive contrast.Discard nutrient solution, cell is washed twice with PBS, ethanol cracking with 95%, centrifugal 3 minutes of 13000rpm, to dissolve with 0.05M acetate buffer solution (0.5ml) after the supernatant vacuum-drying, (Amersham USA) detects the cAMP level, and result's fusion rotein of the present invention as shown in Figure 3 is basic identical at external influence and commercial people GLP-1 (7-36) to the cAMP level with the cAMPBiotrak spa system.

Embodiment 7

Pharmacokinetics in the body of fusion rotein

Pharmacokinetics in the body of fusion rotein: give injection fusion rotein (50nM) in the C57BL/6 mouse vein, respectively at injection back 0min, 1hr, 6hr, 12hr, 24hr, 36hr, 48hr takes a blood sample in the tail vein behind 60hr and the 72hr.4 ℃ of centrifugal separation plasmas detect the PPS601 level with the ELISA method.Pharmacokinetics the results are shown in Figure 4 in the body of fusion rotein (the 2nd G replaces A) GLP-1-intermediate head-glucagon receptor functional zone-1-intermediate head-glucagon receptor functional zone-3-intermediate head-human IgG1 Fc (PPS 601), and the fusion rotein of the present invention transformation period in vivo, more independent GLP-1 obviously prolonged.

Embodiment 8

The ELISA method detects the concentration of fusion rotein in the mouse blood plasma

Identify the concentration of total fusion rotein in the mouse blood plasma with the ELISA method.With the antibody of the special affinity extraction of anti-human IgG gamma chain of PBS dilution (Sigma, USA) 100 μ l (2 μ g/ml) bag is by 96 hole enzyme plate (Nunc-Immunoplate Maxisorp; Nalge NuncInternational, Demark), 4 ℃ are spent the night.After washing 4 times, with 1%BSA-PBS 300 μ l room temperatures sealing 2hr.PPS601 standard substance and serum that adding is diluted with 0.5%BSA-PBS, room temperature effect 2hr.After washing four times, (JacksonImmunoResearch, USA), room temperature effect 1hr adds TMB to the goat anti-human igg of adding HRP mark then, room temperature effect 20 minutes.With measuring the 450-570nm value after the sulfuric acid stopped reaction.

Embodiment 9

Fusion rotein is to the influence of the anti-sugared ability of mouse

Give the mouse of fusion rotein anti-sugar experiment: the fusion rotein (4ug/kg that gives mouse (C57BL/6) the subcutaneous injection various dose that spend the night (16-18h) go on a hunger strike, 16ug/kg, 80ug/kg and 1mg/kg) or physiological saline, behind injection 30min and the 24h, press 1.5mg/g body weight abdominal injection glucose, and respectively at injection back 0,10,20,30,60,90 and 120min after take blood sample from the tail point.Detect glucose level in the blood with the glucose table by the glucolase method.The anti-sugared experimental result of mouse that gives fusion rotein PPS 601 is seen Fig. 5, give fusion rotein of the present invention after, the anti-sugared ability of mouse obviously strengthens.

Sequence table

＜110〉Northeast Normal University

＜120〉GLP-1 fusion rotein and preparation method thereof and medicinal use

<130>GLP-1

<160>37

<170>PatentIn version 3.3

<210>1

<211>31

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

＜223〉the 2nd Xaa is Ala, Gly, Ser or Thr;

<220>

<221>misc_feature

<222>(3)..(3)

＜223〉the 3rd Xaa is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(5)..(5)

＜223〉the 5th Xaa is Thr, Arg or Ile;

<220>

<221>misc_feature

<222>(6)..(6)

＜223〉the 6th Xaa is Phe, Tyr or Leu;

<220>

<221>misc_feature

<222>(8)..(8)

＜223〉the 8th Xaa is Ser or Asn;

<220>

<221>misc_feature

<222>(9)..(9)

＜223〉the 9th Xaa is Asp or Asn;

<220>

<221>misc_feature

<222>(10)..(10)

＜223〉the 10th Xaa is Val, Ile, Met or Ala;

<220>

<221>misc_feature

<222>(11)..(11)

＜223〉the 11st Xaa is Ser, Thr, Ala or Asp;

<220>

<221>misc_feature

<222>(12)..(12)

＜223〉the 12nd Xaa is Ser, Gln, Glu, Asn or Thr;

<220>

<221>misc_feature

<222>(13)..(13)

＜223〉the 13rd Xaa is Tyr, Phe, Gln, His or Leu;

<220>

<221>misc_feature

<222>(14)..(14)

＜223〉the 14th Xaa is Leu, Thr or Ser;

<220>

<221>misc_feature

<222>(15)..(15)

＜223〉the 15th Xaa is Glu, Gln, Asn, Asp, Arg or Lys;

<220>

<221>misc_feature

<222>(16)..(16)

＜223〉the 16th Xaa is Gly, Glu, Asp, Gln, Asn, Arg or Lys;

<220>

<221>misc_feature

<222>(17)..(17)

＜223〉the 17th Xaa is Gln, Lys, Leu or Phe;

<220>

<221>misc_feature

<222>(18)..(18)

＜223〉the 18th Xaa is Ala or Lys;

<220>

<221>misc_feature

<222>(19)..(19)

＜223〉the 19th Xaa is Ala, Thr, Ile or Ser;

<220>

<221>misc_feature

<222>(20)..(20)

＜223〉the 20th Xaa is Lys, Arg or Gln;

<220>

<221>misc_feature

<222>(21)..(21)

＜223〉the 21st Xaa is Glu, Asp, Asn, Ala, Ser, Lys or Arg;

<220>

<221>misc_feature

<222>(23)..(23)

＜223〉the 23rd Xaa is Ile or Val;

<220>

<221>misc_feature

<222>(24)..(24)

＜223〉the 24th Xaa is Ala, Ser, Asp, Glu, Gly or Thr;

<220>

<221>misc_feature

<222>(25)..(25)

＜223〉the 25th Xaa is Trp, Arg, Lys or Ser;

<220>

<221>misc_feature

<222>(26)..(26)

＜223〉the 26th Xaa is Val, Lys, Ile, Ser or Ala;

<220>

<221>misc_feature

<222>(28)..(28)

＜223〉the 28th Xaa is Lys, Arg, Asn, Gln, Ser, Ala or Thr;

<220>

<221>misc_feature

<222>(29)..(29)

＜223〉the 29th Xaa is Gly, Tyr or Ser;

<220>

<221>misc_feature

<222>(30)..(30)

＜223〉the 30th Xaa is Arg, Lys, Gln, Asp, Asn, Gly, Ala or Pro;

<220>

<221>misc_feature

<222>(31)..(31)

＜223〉the 31st Xaa is Gly, Pro, Val, Arg, Lys or Ala or be removed;

<400>1

His Xaa Xaa Gly Xaa Xaa Thr Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5 10 15

Xaa Xaa Xaa Xaa Xaa Phe Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa

20 25 30

<210>2

<211>452

<212>PRT

＜213〉people

<400>2

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Val Met Tyr Thr Val Gly Tyr Ser Leu Ser Leu

115 120 125

Gly Ala Leu Leu Leu Ala Leu Ala Ile Leu Gly Gly Leu Ser Lys Leu

130 135 140

His Cys Thr Arg Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val

145 150 155 160

Leu Lys Ala Ser Ser Val Leu Val Ile Asp Gly Leu Leu Arg Thr Arg

165 170 175

Tyr Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu Ser

180 185 190

Asp Gly Ala Val Ala Gly Cys Arg Val Ala Ala Val Phe Met Gln Tyr

195 200 205

Gly Ile Val Ala Asn Tyr Cys Trp Leu Leu Val Glu Gly Leu Tyr Leu

210 215 220

His Asn Leu Leu Gly Leu Ala Thr Leu Pro Glu Arg Ser Phe Phe Ser

225 230 235 240

Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met Leu Phe Val Val Pro

245 250 255

Trp Ala Val Val Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser

260 265 270

Asn Asp Asn Met Gly Phe Trp Trp Ile Leu Arg Phe Pro Val Phe Leu

275 280 285

Ala Ile Leu Ile Asn Phe Phe Ile Phe Val Arg Ile Val Gln Leu Leu

290 295 300

Val Ala Lys Leu Arg Ala Arg Gln Met His His Thr Asp Tyr Lys Phe

305 310 315 320

Arg Leu Ala Lys Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Val His

325 330 335

Glu Val Val Phe Ala Phe Val Thr Asp Glu His Ala Gln Gly Thr Leu

340 345 350

Arg Ser Ala Lys Leu Phe Phe Asp Leu Phe Leu Ser Ser Phe Gln Gly

355 360 365

Leu Leu Val Ala Val Leu Tyr Cys Phe Leu Asn Lys Glu Val Gln Ser

370 375 380

Glu Leu Arg Arg Arg Trp His Arg Trp Arg Leu Gly Lys Val Leu Trp

385 390 395 400

Glu Glu Arg Asn Thr Ser Asn His Arg Ala Ser Ser Ser Pro Gly His

405 410 415

Gly Pro Pro Ser Lys Glu Leu Gln Phe Gly Arg Gly Gly Gly Ser Gln

420 425 430

Asp Ser Ser Ala Glu Thr Pro Leu Ala Gly Gly Leu Pro Arg Leu Ala

435 440 445

Glu Ser Pro Phe

450

<210>3

<211>117

<212>PRT

＜213〉people

<400>3

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln

115

<210>4

<211>32

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

＜223〉the 1st Xaa is Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val Leu LysAla Ser

Ser Val Leu Val, from the N-end, all amino acid can be removed one by one;

<220>

<221>misc_feature

<222>(32)..(32)

＜223〉the 32nd Xaa is Cys Arg Val Ala Ala Val Phe Met Gln Tyr Gly Ile Val AlaAsn Tyr

Cys Trp Leu Leu Val Glu Gly Leu Tyr Leu, from the C-end, all amino acid can be removed one by one;

<400>4

Xaa Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser Gln Lys Ile Gly Asp

1 5 10 15

Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly Ala Val Ala Gly Xaa

20 25 30

<210>5

<211>20

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

＜223〉the 1st Xaa is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPhe Val

Val Pro Trp Ala Val Val, from the N-end, all amino acid can be removed one by one;

<220>

<221>misc_feature

<222>(20)..(20)

＜223〉the 20th Xaa is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

Phe Ile Phe Val Arg Ile Val, from the C-end, all amino acid can be removed one by one;

<400>5

Xaa Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser Asn Asp Asn

1 5 10 15

Met Gly Phe Xaa

20

<210>6

<211>20

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

＜223〉the 1st Xaa is Thr Leu Thr Leu Ile Pro Leu Leu Gly Val His Glu Val Val PheAla

Phe Val Thr, from the N-end, all amino acid can be removed one by one;

<220>

<221>misc_feature

<222>(20)..(20)

＜223〉the 20th Xaa is Leu Phe Leu Ser Ser Phe Gln Gly Leu Leu Val Ala Val LeuTyr Cys

Phe Leu Asn, from the C-end, all amino acid can be removed one by one;

<400>6

Xaa Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser Asn Asp Asn

1 5 10 15

Met Gly Phe Xaa

20

<210>7

<211>55

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

＜223〉the 1st Xaa is Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val Leu Lys AlaSer

Ser Val Leu Val, from the N-end, all amino acid can be removed one by one;

<220>

<221>misc_feature

<222>(32)..(32)

<220>

<221>misc_feature

<222>(33)..(33)

＜223〉the 33rd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer

<220>

<221>misc_feature

<222>(34)..(34)

＜223〉the 34th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed

<220>

<221>misc_feature

<222>(35)..(35)

＜223〉the 35th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed

<220>

<221>misc_feature

<222>(36)..(36)

＜223〉the 36th Xaa is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPhe Val

<220>

<221>misc_feature

<222>(55)..(55)

＜223〉the 55th Xaa is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>7

Xaa Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser Gln Lys Ile Gly Asp

1 5 10 15

Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly Ala Val Ala Gly Xaa

20 25 30

Xaa Xaa Xaa Xaa Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser

35 40 45

Asn Asp Asn Met Gly Phe Xaa

50 55

<210>8

<211>53

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

Ser Val Leu Val, from the N-end, all amino acid can be removed one by one;

<220>

<221>misc_feature

<222>(32)..(32)

<220>

<221>misc_feature

<222>(33)..(33)

<220>

<221>misc_feature

<222>(34)..(34)

<220>

<221>misc_feature

<222>(35)..(35)

<220>

<221>misc_feature

<222>(36)..(36)

<220>

<221>misc_feature

<222>(53)..(53)

＜223〉the 53rd Xaa is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>8

Xaa Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser Gln Lys Ile Gly Asp

1 5 10 15

Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly Ala Val Ala Gly Xaa

20 25 30

Xaa Xaa Xaa Xaa Asp Glu His Ala Gln Gly Thr Leu Arg Ser Ala Lys

35 40 45

Leu Phe Phe Asp Xaa

50

<210>9

<211>41

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

＜223〉the 1st Xaa is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met Leu PheVal

<220>

<221>misc_feature

<222>(20)..(20)

<220>

<221>misc_feature

<222>(21)..(21)

＜223〉the 21st Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(22)..(22)

＜223〉the 22nd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(23)..(23)

＜223〉the 23rd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(24)..(24)

＜223〉the 24th Xaa is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPhe Val

<220>

<221>misc_feature

<222>(41)..(41)

＜223〉the 41st Xaa is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>9

Xaa Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser Asn Asp Asn

1 5 10 15

Met Gly Phe Xaa Xaa Xaa Xaa Xaa Asp Glu His Ala Gln Gly Thr Leu

20 25 30

Arg Ser Ala Lys Leu Phe Phe Asp Xaa

35 40

<210>10

<211>76

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

Ser Val Leu Val, from the N-end, all amino acid can be removed one by one;

<220>

<221>misc_feature

<222>(32)..(32)

<220>

<221>misc_feature

<222>(33)..(33)

＜223〉the 33rd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(34)..(34)

＜223〉the 34th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(35)..(35)

＜223〉the 35th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(36)..(36)

<220>

<221>misc_feature

<222>(55)..(55)

<220>

<221>misc_feature

<222>(56)..(56)

＜223〉the 56th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(57)..(57)

＜223〉the 57th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(58)..(58)

＜223〉the 58th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(59)..(59)

＜223〉the 59th Xaa is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPhe Val

<220>

<221>misc_feature

<222>(76)..(76)

＜223〉the 76th Xaa is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>10

Xaa Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser Gln Lys Ile Gly Asp

1 5 10 15

Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly Ala Val Ala Gly Xaa

20 25 30

Xaa Xaa Xaa Xaa Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser

35 40 45

Asn Asp Asn Met Gly Phe Xaa Xaa Xaa Xaa Xaa Asp Glu His Ala Gln

50 55 60

Gly Thr Leu Arg Ser Ala Lys Leu Phe Phe Asp Xaa

65 70 75

<210>11

<211>152

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

＜223〉the 118th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(119)..(119)

＜223〉the 119th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(120)..(120)

＜223〉the 120th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(121)..(121)

＜223〉the 121st Xaa is Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val Leu LysAla Ser

Ser Val Leu Val, from the N-end, all amino acid can be removed one by one;

<220>

<221>misc_feature

<222>(152)..(152)

＜223〉the 152nd Xaa is Cys Arg Val Ala Ala Val Phe Met Gln Tyr Gly Ile Val AlaAsn Tyr

<400>11

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Ile Asp Gly Leu Leu Arg Thr

115 120 125

Arg Tyr Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu

130 135 140

Ser Asp Gly Ala Val Ala Gly Xaa

145 150

<210>12

<211>140

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

＜223〉the 121st Xaa is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPhe Val

<220>

<221>misc_feature

<222>(140)..(140)

＜223〉the 140th Xaa is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>12

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Lys Cys Leu Phe Glu Asn Val

115 120 125

Gln Cys Trp Thr Ser Asn Asp Asn Met Gly Phe Xaa

130 135 140

<210>13

<211>138

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

<220>

<221>misc_feature

<222>(138)..(138)

＜223〉the 138th Xaa is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>13

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Asp Glu His Ala Gln Gly Thr

115 120 125

Leu Arg Ser Ala Lys Leu Phe Phe Asp Xaa

130 135

<210>14

<211>175

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

Ser Val Leu Val, from the N-end, all amino acid can be removed one by one;

<220>

<221>misc_feature

<222>(152)..(152)

<220>

<221>misc_feature

<222>(153)..(153)

＜223〉the 153rd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(154)..(154)

＜223〉the 154th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(155)..(155)

＜223〉the 155th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(156)..(156)

＜223〉the 156th Xaa is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPhe Val

<220>

<221>misc_feature

<222>(175)..(175)

＜223〉the 175th Xaa is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>14

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Ile Asp Gly Leu Leu Arg Thr

115 120 125

Arg Tyr Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu

130 135 140

Ser Asp Gly Ala Val Ala Gly Xaa Xaa Xaa Xaa Xaa Lys Cys Leu Phe

145 150 155 160

Glu Asn Val Gln Cys Trp Thr Ser Asn Asp Asn Met Gly Phe Xaa

165 170 175

<210>15

<211>173

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

Ser Val Leu Val, from the N-end, all amino acid can be removed one by one;

<220>

<221>misc_feature

<222>(152)..(152)

<220>

<221>misc_feature

<222>(153)..(153)

<220>

<221>misc_feature

<222>(154)..(154)

<220>

<221>misc_feature

<222>(155)..(155)

<220>

<221>misc_feature

<222>(156)..(156)

<220>

<221>misc_feature

<222>(173)..(173)

＜223〉the 173rd Xaa is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>15

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Ile Asp Gly Leu Leu Arg Thr

115 120 125

Arg Tyr Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu

130 135 140

Ser Asp Gly Ala Val Ala Gly Xaa Xaa Xaa Xaa Xaa Asp Glu His Ala

145 150 155 160

Gln Gly Thr Leu Arg Ser Ala Lys Leu Phe Phe Asp Xaa

165 170

<210>16

<211>161

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

<220>

<221>misc_feature

<222>(140)..(140)

<220>

<221>misc_feature

<222>(141)..(141)

＜223〉the 141st Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(142)..(142)

＜223〉the 142nd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(143)..(143)

＜223〉the 143rd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(144)..(144)

＜223〉the 144th Xaa is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPhe Val

<220>

<221>misc_feature

<222>(161)..(161)

＜223〉the 161st Xaa is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>16

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Lys Cys Leu Phe Glu Asn Val

115 120 125

Gln Cys Trp Thr Ser Asn Asp Asn Met Gly Phe Xaa Xaa Xaa Xaa Xaa

130 135 140

Asp Glu His Ala Gln Gly Thr Leu Arg Ser Ala Lys Leu Phe Phe Asp

145 150 155 160

Xaa

<210>17

<211>196

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

Ser Val Leu Val, from the N-end, all amino acid can be removed one by one;

<220>

<221>misc_feature

<222>(152)..(152)

<220>

<221>misc_feature

<222>(153)..(153)

<220>

<221>misc_feature

<222>(154)..(154)

<220>

<221>misc_feature

<222>(155)..(155)

<220>

<221>misc_feature

<222>(156)..(156)

<220>

<221>misc_feature

<222>(175)..(175)

<220>

<221>misc_feature

<222>(176)..(176)

＜223〉the 176th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(177)..(177)

＜223〉the 177th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(178)..(178)

＜223〉the 178th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(179)..(179)

＜223〉the 179th Xaa is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPhe Val

<220>

<221>misc_feature

<222>(196)..(196)

＜223〉the 196th Xaa is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>17

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

ln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Ile Asp Gly Leu Leu Arg Thr

115 120 125

Arg Tyr Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu

130 135 140

Ser Asp Gly Ala Val Ala Gly Xaa Xaa Xaa Xaa Xaa Lys Cys Leu Phe

145 150 155 160

Glu Asn Val Gln Cys Trp Thr Ser Asn Asp Asn Met Gly Phe Xaa Xaa

165 170 175

Xaa Xaa Xaa Asp Glu His Ala Gln Gly Thr Leu Arg Ser Ala Lys Leu

180 185 190

Phe Phe Asp Xaa

195

<210>18

<211>440

<212>PRT

＜213〉people

<400>18

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser Leu Pro

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Ile Ile Tyr Thr Val Gly

115 120 125

Tyr Ala Leu Ser Phe Ser Ala Leu Val Ile Ala Ser Ala Ile Leu Leu

130 135 140

Gly Phe Arg His Leu His Cys Thr Arg Asn Tyr Ile His Leu Asn Leu

145 150 155 160

Phe Ala Ser Phe Ile Leu Arg Ala Leu Ser Val Phe Ile Lys Asp Ala

165 170 175

Ala Leu Lys Trp Met Tyr Ser Thr Ala Ala Gln Gln His Gln Trp Asp

180 185 190

Gly Leu Leu Ser Tyr Gln Asp Ser Leu Ser Cys Arg Leu Val Phe Leu

195 200 205

Leu Met Gln Tyr Cys Val Ala Ala Asn Tyr Tyr Trp Leu Leu Val Glu

210 215 220

Gly Val Tyr Leu Tyr Thr Leu Leu Ala Phe Ser Val Phe Ser Glu Gln

225 230 235 240

Trp Ile Phe Arg Leu Tyr Val Ser Ile Gly Trp Gly Val Pro Leu Leu

245 250 255

Phe Val Val Pro Trp Gly Ile Val Lys Tyr Leu Tyr Glu Asp Glu Gly

260 265 270

Cys Trp Thr Arg Asn Ser Asn Met Asn Tyr Trp Leu Ile Ile Arg Leu

275 280 285

Pro Ile Leu Phe Ala Ile Gly Val Asn Phe Leu Ile Phe Val Arg Val

290 295 300

Ile Cys Ile Val Val Ser Lys Leu Lys Ala Asn Leu Met Cys Lys Thr

305 310 315 320

Asp Ile Lys Cys Arg Leu Ala Lys Ser Thr Leu Thr Leu Ile Pro Leu

325 330 335

Leu Gly Thr His Glu Val Ile Phe Ala Phe Val Met Asp Glu His Ala

340 345 350

Arg Gly Thr Leu Arg Phe Ile Lys Leu Phe Thr Glu Leu Ser Phe Thr

355 360 365

Ser Phe Gln Gly Leu Met Val Ala Ile Leu Tyr Cys Phe Val Asn Asn

370 375 380

Glu Val Gln Leu Glu Phe Arg Lys Ser Trp Glu Arg Trp Arg Leu Glu

385 390 395 400

His Leu His Ile Gln Arg Asp Ser Ser Met Lys Pro Leu Lys Cys Pro

405 410 415

Thr Ser Ser Leu Ser Ser Gly Ala Thr Ala Gly Ser Ser Met Tyr Thr

420 425 430

Ala Thr Cys Gln Ala Ser Cys Ser

435 440

<210>19

<211>122

<212>PRT

＜213〉people

<400>19

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

yr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser Leu Pro

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr

115 120

<210>20

<21l>78

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

＜223〉the 2nd Xaa is Tyr, Ala or be removed;

<220>

<221>misc_feature

<222>(5)..(5)

＜223〉the 5th Xaa is Leu, Ala, Met or be removed;

<220>

<221>misc_feature

<222>(9)..(9)

＜223〉the 9th Xaa is Ala, Gly or be removed;

<220>

<221>misc_feature

<222>(12)..(12)

＜223〉the 12nd Xaa is Ile, Val, Met or be removed;

<220>

<221>misc_feature

<222>(14)..(14)

＜223〉the 14th Xaa is Leu, Val or be removed;

<220>

<221>misc_feature

<222>(15)..(15)

＜223〉the 15th Xaa is Arg, Lys or be removed;

<220>

<221>misc_feature

<222>(16)..(16)

＜223〉the 16th Xaa is Ala, Ser or be removed;

<220>

<221>misc_feature

<222>(17)..(17)

＜223〉the 17th Xaa is Leu, Ser or be removed;

<220>

<221>misc_feature

<222>(19)..(19)

＜223〉the 19th Xaa is Val, Leu or be removed;

<220>

<221>misc_feature

<222>(20)..(20)

＜223〉the 20th Xaa is Phe, Leu or be removed;

<220>

<221>misc_feature

<222>(21)..(21)

＜223〉the 21st Xaa is Ile, Val or be removed;

<220>

<221>misc_feature

<222>(22)..(22)

＜223〉the 22nd Xaa is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(24)..(24)

＜223〉the 24th Xaa is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(25)..(25)

＜223〉the 25th Xaa is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(27)..(27)

＜223〉the 27th Xaa is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(28)..(28)

＜223〉the 28th Xaa is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

＜223〉the 29th Xaa is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(30)..(30)

＜223〉the 30th Xaa is Tyr or Asn;

<220>

<221>misc_feature

<222>(31)..(31)

＜223〉the 31st Xaa is Ser or Arg;

<220>

<221>misc_feature

<222>(32)..(32)

＜223〉the 32nd Xaa is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(33)..(33)

＜223〉the 33rd Xaa is Lys, Arg or removal;

<220>

<221>misc_feature

<222>(34)..(34)

＜223〉the 34th Xaa is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(35)..(35)

＜223〉the 35th Xaa is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(36)..(36)

＜223〉the 36th Xaa is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(37)..(37)

＜223〉the 37th Xaa is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(38)..(38)

＜223〉the 38th Xaa is His or Leu;

<220>

<221>misc_feature

<222>(39)..(39)

＜223〉the 39th Xaa is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(40)..(40)

＜223〉the 40th Xaa is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(41)..(41)

＜223〉the 41st Xaa is Asp or Ser;

<220>

<221>misc_feature

<222>(42)..(42)

＜223〉the 42nd Xaa is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(43)..(43)

＜223〉the 43rd Xaa is Arg or removal;

<220>

<22l>misc_feature

<222>(44)..(44)

＜223〉the 44th Xaa is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(46)..(46)

＜223〉the 46th Xaa is Ser or Asp;

<220>

<221>misc_feature

<222>(47)..(47)

＜223〉the 47th Xaa is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(48)..(48)

＜223〉the 48th Xaa is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(49)..(49)

＜223〉the 49th Xaa is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(50)..(50)

＜223〉the 50th Xaa is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(51)..(51)

＜223〉the 51st Xaa is Leu, Ala, Thr or Val;

<220>

<221>misc_feature

<222>(52)..(52)

＜223〉the 52nd Xaa is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(53)..(53)

＜223〉the 53rd Xaa is Cys or is removed;

<220>

<221>misc_feature

<222>(54)..(54)

＜223〉the 54th Xaa is Arg or is removed;

<220>

<221>misc_feature

<222>(55)..(55)

＜223〉the 55th Xaa is Leu, Val, Ala, Ser or be removed;

<220>

<221>misc_feature

<222>(56)..(56)

＜223〉the 56th Xaa is Val, Ala or be removed;

<220>

<221>misc_feature

<222>(57)..(57)

＜223〉the 57th Xaa is Phe, Ala, Thr, Met or be removed;

<220>

<221>misc_feature

<222>(58)..(58)

＜223〉the 58th Xaa is Leu, Val or be removed;

<220>

<221>misc_feature

<222>(59)..(59)

＜223〉the 59th Xaa is Leu, Phe, Met or be removed;

<220>

<221>misc_feature

<222>(63)..(63)

＜223〉the 63rd Xaa is Cys, Gly, Ser or be removed;

<220>

<221>misc_feature

<222>(64)..(64)

＜223〉the 64th Xaa is Val, Ile, Met or be removed;

<220>

<221>misc_feature

<222>(65)..(65)

＜223〉the 65th Xaa is Ala, Val, Met, Ile or be removed;

<220>

<221>misc_feature

<222>(69)..(69)

＜223〉the 69th Xaa is Tyr, Cys or be removed;

<220>

<221>misc_feature

<222>(76)..(76)

＜223〉the 76th Xaa is Val or Leu or is removed;

<400>20

Asn Xaa Ile His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa

1 5 10 15

Xaa Ser Xaa Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

20 25 30

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa

35 40 45

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa

50 55 60

Xaa Ala Asn Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu

65 70 75

<210>21

<211>64

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

＜223〉the 2nd Xaa is Arg or Ser or is removed;

<220>

<221>misc_feature

<222>(5)..(5)

＜223〉the 5th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(6)..(6)

＜223〉the 6th Xaa is Ser, Gly or Cys or be removed;

<220>

<221>misc_feature

<222>(11)..(11)

＜223〉the 11st Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(13)..(13)

＜223〉the 13rd Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(17)..(17)

＜223〉the 17th Xaa is Val, Leu or Ile or be removed;

<220>

<221>misc_feature

<222>(20)..(20)

＜223〉the 20th Xaa is Gly, Ala, Met or Val or be removed;

<220>

<221>misc_feature

<222>(21)..(21)

＜223〉the 21st Xaa is Ile, Val, Thr or Ala or be removed;

<220>

<221>misc_feature

<222>(22)..(22)

＜223〉the 22nd Xaa is Val or is removed;

<220>

<221>misc_feature

<222>(23)..(23)

＜223〉the 23rd Xaa is Lys or is removed;

<220>

<221>misc_feature

<222>(24)..(24)

＜223〉the 24th Xaa is Tyr or Cys;

<220>

<221>misc_feature

<222>(26)..(26)

＜223〉the 26th Xaa is Tyr or Phe;

<220>

<221>misc_feature

<222>(28)..(28)

＜223〉the 28th Xaa is Asp or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

＜223〉the 29th Xaa is Glu or Val;

<220>

<221>misc_feature

<222>(30)..(30)

＜223〉the 30th Xaa is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(33)..(33)

＜223〉the 33rd Xaa is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(34)..(34)

＜223〉the 34th Xaa is Arg or Ser;

<220>

<221>misc_feature

<222>(36)..(36)

＜223〉the 36th Xaa is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(39)..(39)

＜223〉the 39th Xaa is Asn or Gly or is removed;

<220>

<221>misc_feature

<222>(40)..(40)

＜223〉the 40th Xaa is Tyr or Phe or is removed;

<220>

<221>misc_feature

<222>(42)..(42)

＜223〉the 42nd Xaa is Leu or Trp or is removed;

<220>

<221>misc_feature

<222>(44)..(44)

＜223〉the 44th Xaa is Ile or Leu or is removed;

<220>

<221>misc_feature

<222>(46)..(46)

＜223〉the 46th Xaa is Leu, Phe, Ile or Ser or be removed;

<220>

<221>misc_feature

<222>(48)..(48)

＜223〉the 48th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(49)..(49)

＜223〉the 49th Xaa is Leu or Phe or is removed;

<220>

<221>misc_feature

<222>(50)..(50)

＜223〉the 50th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(53)..(53)

＜223〉the 53rd Xaa is Gly or Leu or is removed;

<220>

<221>misc_feature

<222>(54)..(54)

＜223〉the 54th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(57)..(57)

＜223〉the 57th Xaa is Leu, Phe or Ile or be removed;

<220>

<221>misc_feature

<222>(62)..(62)

＜223〉the 62nd Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(63)..(63)

＜223〉the 63rd Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(64)..(64)

＜223〉the 64th Xaa is Gln or Cys or is removed;

<400>21

Phe Xaa Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val

1 5 10 15

Xaa Pro Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp

20 25 30

Xaa Xaa Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa

35 40 45

Xaa Xaa Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa

50 55 60

<210>22

<211>57

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(11)..(11)

＜223〉the 11st Xaa is Thr, Val or Ile or be removed;

<220>

<221>misc_feature

<222>(15)..(15)

＜223〉the 15th Xaa is Ile, Val, Leu or Ala or be removed;

<220>

<221>misc_feature

<222>(20)..(20)

＜223〉the 20th Xaa is Met, Thr, Ile, Ala or be removed;

<220>

<221>misc_feature

<222>(23)..(23)

＜223〉the 23rd Xaa is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(24)..(24)

＜223〉the 24th Xaa is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(25)..(25)

＜223〉the 25th Xaa is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(26)..(26)

＜223〉the 26th Xaa is Gly or Ser;

<220>

<221>misc_feature

<222>(27)..(27)

＜223〉the 27th Xaa is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(30)..(30)

＜223〉the 30th Xaa is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(31)..(31)

＜223〉the 31st Xaa is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(32)..(32)

＜223〉the 32nd Xaa is Lys or Arg;

<220>

<221>misc_feature

<222>(35)..(35)

＜223〉the 35th Xaa is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(36)..(36)

＜223〉the 36th Xaa is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(38)..(38)

＜223〉the 38th Xaa is Ser, Phe or Leu or removal Leu;

<220>

<221>misc_feature

<222>(39)..(39)

＜223〉the 39th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(40)..(40)

＜223〉the 40th Xaa is Thr, Ser or Gly or be removed;

<220>

<221>misc_feature

<222>(45)..(45)

＜223〉the 45th Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(46)..(46)

＜223〉the 46th Xaa is Met or Leu or is removed;

<220>

<221>misc_feature

<222>(49)..(49)

＜223〉the 49th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(54)..(54)

＜223〉the 54th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(56)..(56)

＜223〉the 56th Xaa is Asn or Lys or is removed;

<400>22

Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa Phe

1 5 10 15

Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg Xaa Xaa Xaa

20 25 30

Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val Ala

35 40 45

Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

50 55

<210>23

<211>145

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

＜223〉the 2nd Xaa is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(5)..(5)

＜223〉the 5th Xaa is Leu, Ala or Met or be removed;

<220>

<221>misc_feature

<222>(9)..(9)

＜223〉the 9th Xaa is Ala or Gly or is removed;

<220>

<221>misc_feature

<222>(12)..(12)

＜223〉the 12nd Xaa is Ile, Val or Met or be removed;

<220>

<221>misc_feature

<222>(14)..(14)

＜223〉the 14th Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(15)..(15)

＜223〉the 15th Xaa is Arg or Lys or is removed;

<220>

<221>misc_feature

<222>(16)..(16)

＜223〉the 16th Xaa is Ala or Ser or is removed;

<220>

<221>misc_feature

<222>(17)..(17)

＜223〉the 17th Xaa is Leu or Ser or is removed;

<220>

<221>misc_feature

<222>(19)..(19)

＜223〉the 19th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(20)..(20)

＜223〉the 20th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(21)..(21)

＜223〉the 21st Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(22)..(22)

＜223〉the 22nd Xaa is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(24)..(24)

＜223〉the 24th Xaa is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(25)..(25)

＜223〉the 25th Xaa is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(27)..(27)

＜223〉the 27th Xaa is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(28)..(28)

＜223〉the 28th Xaa is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

＜223〉the 29th Xaa is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(30)..(30)

＜223〉the 30th Xaa is Tyr or Asn;

<220>

<221>misc_feature

<222>(31)..(31)

＜223〉the 31st Xaa is Ser or Arg;

<220>

<221>misc_feature

<222>(32)..(32)

＜223〉the 32nd Xaa is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(33)..(33)

＜223〉the 33rd Xaa is Lys or Arg or skips;

<220>

<221>misc_feature

<222>(34)..(34)

＜223〉the 34th Xaa is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(35)..(35)

＜223〉the 35th Xaa is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(36)..(36)

＜223〉the 36th Xaa is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(37)..(37)

＜223〉the 37th Xaa is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(38)..(38)

＜223〉the 38th Xaa is His or Leu;

<220>

<221>misc_feature

<222>(39)..(39)

＜223〉the 39th Xaa is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(40)..(40)

＜223〉the 40th Xaa is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(41)..(41)

＜223〉the 41st Xaa is Asp or Ser;

<220>

<221>misc_feature

<222>(42)..(42)

＜223〉the 42nd Xaa is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(43)..(43)

＜223〉the 43rd Xaa is Arg or skips;

<220>

<221>misc_feature

<222>(44)..(44)

＜223〉the 44th Xaa is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(46)..(46)

＜223〉the 46th Xaa is Ser or Asp;

<220>

<221>misc_feature

<222>(47)..(47)

＜223〉the 47th Xaa is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(48)..(48)

＜223〉the 48th Xaa is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(49)..(49)

＜223〉the 49th Xaa is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(50)..(50)

＜223〉the 50th Xaa is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(51)..(51)

＜223〉the 51st Xaa is Leu, Ala, Thr or Val;

<220>

<221>misc_feature

<222>(52)..(52)

＜223〉the 52nd Xaa is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(53)..(53)

＜223〉the 53rd Xaa is Cys or is removed;

<220>

<221>misc_feature

<222>(54)..(54)

＜223〉the 54th Xaa is Arg or is removed;

<220>

<221>misc_feature

<222>(55)..(55)

＜223〉the 55th Xaa is Leu, Val, Ala or Ser or be removed;

<220>

<221>misc_feature

<222>(56)..(56)

＜223〉the 56th Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(57)..(57)

＜223〉the 57th Xaa is Phe, Ala, Thr or Met or be removed;

<220>

<221>misc_feature

<222>(58)..(58)

＜223〉the 58th Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(59)..(59)

＜223〉the 59th Xaa is Leu, Phe or Met or be removed;

<220>

<221>misc_feature

<222>(63)..(63)

＜223〉the 63rd Xaa is Cys, Gly or Ser or be removed;

<220>

<221>misc_feature

<222>(64)..(64)

＜223〉the 64th Xaa is Val, Ile or Met or be removed;

<220>

<221>misc_feature

<222>(65)..(65)

＜223〉the 65th Xaa is Ala, Val, Met or Ile or be removed;

<220>

<221>misc_feature

<222>(69)..(69)

＜223〉the 69th Xaa is Tyr or Cys or is removed;

<220>

<221>misc_feature

<222>(76)..(76)

＜223〉the 76th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(79)..(79)

＜223〉the 79th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(80)..(80)

＜223〉the 80th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(81)..(81)

＜223〉the 81st Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(83)..(83)

＜223〉the 83rd Xaa is Arg or Ser or is removed;

<220>

<221>misc_feature

<222>(86)..(86)

＜223〉the 86th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(87)..(87)

＜223〉the 87th Xaa is Ser, Gly or Cys or be removed;

<220>

<221>misc_feature

<222>(92)..(92)

＜223〉the 92nd Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(94)..(94)

＜223〉the 94th Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(98)..(98)

＜223〉the 98th Xaa is Val, Leu or Ile or be removed;

<220>

<221>misc_feature

<222>(101)..(101)

＜223〉the 101st Xaa is Gly, Ala, Met or Val or be removed;

<220>

<221>misc_feature

<222>(102)..(102)

＜223〉the 102nd Xaa is Ile, Val, Thr or Ala or be removed;

<220>

<221>misc_feature

<222>(103)..(103)

＜223〉the 103rd Xaa is Val or is removed;

<220>

<221>misc_feature

<222>(104)..(104)

＜223〉the 104th Xaa is Lys or is removed;

<220>

<221>misc_feature

<222>(105)..(105)

＜223〉the 105th Xaa is Tyr or Cys;

<220>

<221>misc_feature

<222>(107)..(107)

＜223〉the 107th Xaa is Tyr or Phe;

<220>

<221>misc_feature

<222>(109)..(109)

＜223〉the 109th Xaa is Asp or Asn;

<220>

<221>misc_feature

<222>(110)..(110)

＜223〉the 110th Xaa is Glu or Val;

<220>

<221>misc_feature

<222>(111)..(111)

＜223〉the 111st Xaa is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(114)..(114)

＜223〉the 114th Xaa is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(115)..(115)

＜223〉the 115th Xaa is Arg or Ser:

<220>

<221>misc_feature

<222>(117)..(117)

＜223〉the 117th Xaa is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(120)..(120)

＜223〉the 120th Xaa is Asn or Gly or is removed;

<220>

<221>misc_feature

<222>(121)..(121)

＜223〉the 121st Xaa is Tyr or Phe or is removed;

<220>

<221>misc_feature

<222>(123)..(123)

＜223〉the 123rd Xaa is Leu or Trp or is removed;

<220>

<221>misc_feature

<222>(125)..(125)

＜223〉the 125th Xaa is Ile or Leu or is removed;

<220>

<221>misc_feature

<222>(127)..(127)

＜223〉the 127th Xaa is Leu, Phe, Ile or Ser or be removed;

<220>

<221>misc_feature

<222>(129)..(129)

＜223〉the 129th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

＜223〉the 130th Xaa is Leu or Phe or is removed;

<220>

<221>misc_feature

<222>(131)..(131)

＜223〉the 131st Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(134)..(134)

＜223〉the 134th Xaa is Gly or Leu or is removed;

<220>

<221>misc_feature

<222>(135)..(135)

＜223〉the 135th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(138)..(138)

＜223〉the 138th Xaa is Leu, Phe or Ile or be removed;

<220>

<221>misc_feature

<222>(143)..(143)

＜223〉the 143rd Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(144)..(144)

＜223〉the 144th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(145)..(145)

＜223〉the 145th Xaa is Gln or Cys or is removed;

<400>23

Asn Xaa Ile His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa

1 5 10 15

Xaa Ser Xaa Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

20 25 30

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa

35 40 45

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa

50 55 60

Xaa Ala Asn Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa

65 70 75 80

Xaa Phe Xaa Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe

85 90 95

Val Xaa Pro Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys

100 105 110

Trp Xaa Xaa Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro

115 120 125

Xaa Xaa Xaa Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa

130 135 140

Xaa

145

<210>24

<211>138

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

＜223〉the 2nd Xaa is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(5)..(5)

＜223〉the 5th Xaa is Leu, Ala or Met or be removed;

<220>

<221>misc_feature

<222>(9)..(9)

＜223〉the 9th Xaa is Ala or Gly or is removed;

<220>

<221>misc_feature

<222>(12)..(12)

＜223〉the 12nd Xaa is Ile, Val or Met or be removed;

<220>

<221>misc_feature

<222>(14)..(14)

＜223〉the 14th Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(15)..(15)

＜223〉the 15th Xaa is Arg or Lys or is removed;

<220>

<221>misc_feature

<222>(16)..(16)

＜223〉the 16th Xaa is Ala or Ser or is removed;

<220>

<221>misc_feature

<222>(17)..(17)

＜223〉the 17th Xaa is Leu or Ser or is removed;

<220>

<221>misc_feature

<222>(19)..(19)

＜223〉the 19th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(20)..(20)

＜223〉the 20th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(21)..(21)

＜223〉the 21st Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(22)..(22)

＜223〉the 22nd Xaa is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(24)..(24)

＜223〉the 24th Xaa is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(25)..(25)

＜223〉the 25th Xaa is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(27)..(27)

＜223〉the 27th Xaa is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(28)..(28)

＜223〉the 28th Xaa is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

＜223〉the 29th Xaa is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(30)..(30)

＜223〉the 30th Xaa is Tyr or Asn;

<220>

<221>misc_feature

<222>(31)..(31)

＜223〉the 31st Xaa is Ser or Arg;

<220>

<221>misc_feature

<222>(32)..(32)

＜223〉the 32nd Xaa is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(33)..(33)

＜223〉the 33rd Xaa is Lys or Arg or skips;

<220>

<221>misc_feature

<222>(34)..(34)

＜223〉the 34th Xaa is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(35)..(35)

＜223〉the 35th Xaa is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(36)..(36)

＜223〉the 36th Xaa is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(37)..(37)

＜223〉the 37th Xaa is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(38)..(38)

＜223〉the 38th Xaa is His or Leu;

<220>

<221>misc_feature

<222>(39)..(39)

＜223〉the 39th Xaa is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(40)..(40)

＜223〉the 40th Xaa is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(41)..(41)

＜223〉the 41st Xaa is Asp or Ser;

<220>

<221>misc_feature

<222>(42)..(42)

＜223〉the 42nd Xaa is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(43)..(43)

＜223〉the 43rd Xaa is Arg or skips;

<220>

<221>misc_feature

<222>(44)..(44)

＜223〉the 44th Xaa is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(46)..(46)

＜223〉the 46th Xaa is Ser or Asp;

<220>

<221>misc_feature

<222>(47)..(47)

＜223〉the 47th Xaa is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(48)..(48)

＜223〉the 48th Xaa is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(49)..(49)

＜223〉the 49th Xaa is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(50)..(50)

＜223〉the 50th Xaa is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(51)..(51)

＜223〉the 51st Xaa is Leu, Ala, Thr or Val;

<220>

<221>misc_feature

<222>(52)..(52)

＜223〉the 52nd Xaa is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(53)..(53)

＜223〉the 53rd Xaa is Cys or is removed;

<220>

<221>misc_feature

<222>(54)..(54)

＜223〉the 54th Xaa is Arg or is removed;

<220>

<221>misc_feature

<222>(55)..(55)

＜223〉the 55th Xaa is Leu, Val, Ala or Ser or be removed;

<220>

<221>misc_feature

<222>(56)..(56)

＜223〉the 56th Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(57)..(57)

＜223〉the 57th Xaa is Phe, Ala, Thr or Met or be removed;

<220>

<221>misc_feature

<222>(58)..(58)

＜223〉the 58th Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(59)..(59)

＜223〉the 59th Xaa is Leu, Phe or Met or be removed;

<220>

<221>misc_feature

<222>(63)..(63)

＜223〉the 63rd Xaa is Cys, Gly or Ser or be removed;

<220>

<221>misc_feature

<222>(64)..(64)

＜223〉the 64th Xaa is Val, Ile or Met or be removed;

<220>

<221>misc_feature

<222>(65)..(65)

＜223〉the 65th Xaa is Ala, Val, Met or Ile or be removed;

<220>

<221>misc_feature

<222>(69)..(69)

＜223〉the 69th Xaa is Tyr or Cys or is removed;

<220>

<221>misc_feature

<222>(76)..(76)

＜223〉the 76th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(79)..(79)

<220>

<221>misc_feature

<222>(80)..(80)

<220>

<221>misc_feature

<222>(81)..(81)

<220>

<221>misc_feature

<222>(92)..(92)

＜223〉the 92nd Xaa is Thr, Val or Ile or be removed;

<220>

<221>misc_feature

<222>(96)..(96)

＜223〉the 96th Xaa is Ile, Val, Leu or Ala or be removed;

<220>

<221>misc_feature

<222>(101)..(101)

＜223〉the 101st Xaa is Met, Thr, Ile or Ala or be removed;

<220>

<221>misc_feature

<222>(104)..(104)

＜223〉the 104th Xaa is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(105)..(105)

＜223〉the 105th Xaa is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(106)..(106)

＜223〉the 106th Xaa is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(107)..(107)

＜223〉the 107th Xaa is Gly or Ser;

<220>

<221>misc_feature

<222>(108)..(108)

＜223〉the 108th Xaa is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(111)..(111)

＜223〉the 111st Xaa is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(112)..(112)

＜223〉the 112nd Xaa is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(113)..(113)

＜223〉the 113rd Xaa is Lys or Arg;

<220>

<221>misc_feature

<222>(116)..(116)

＜223〉the 116th Xaa is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(117)..(117)

＜223〉the 117th Xaa is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(119)..(119)

＜223〉the 119th Xaa is Ser, Phe or Leu or removal Leu;

<220>

<221>misc_feature

<222>(120)..(120)

＜223〉the 120th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(121)..(121)

＜223〉the 121st Xaa is Thr, Ser or Gly or be removed;

<220>

<221>misc_feature

<222>(126)..(126)

＜223〉the 126th Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(127)..(127)

＜223〉the 127th Xaa is Met or Leu or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

＜223〉the 130th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(135)..(135)

＜223〉the 135th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(137)..(137)

＜223〉the 137th Xaa is Asn or Lys or is removed;

<400>24

Asn Xaa Ile His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa

1 5 10 15

Xaa Ser Xaa Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

20 25 30

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa

35 40 45

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa

50 55 60

Xaa Ala Asn Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa

65 70 75 80

Xaa Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa

85 90 95

Phe Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg Xaa Xaa

100 105 110

Xaa Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val

115 120 125

Ala Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

130 135

<210>25

<211>124

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

＜223〉the 2nd Xaa is Arg or Ser or is removed;

<220>

<221>misc_feature

<222>(5)..(5)

＜223〉the 5th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(6)..(6)

＜223〉the 6th Xaa is Ser, Gly or Cys or be removed;

<220>

<221>misc_feature

<222>(11)..(11)

＜223〉the 11st Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(13)..(13)

＜223〉the 13rd Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(17)..(17)

＜223〉the 17th Xaa is Val, Leu or Ile or be removed;

<220>

<221>misc_feature

<222>(20)..(20)

＜223〉the 20th Xaa is Gly, Ala, Met or Val or be removed;

<220>

<221>misc_feature

<222>(21)..(21)

＜223〉the 21st Xaa is Ile, Val, Thr or Ala or be removed;

<220>

<221>misc_feature

<222>(22)..(22)

＜223〉the 22nd Xaa is Val or is removed;

<220>

<221>misc_feature

<222>(23)..(23)

＜223〉the 23rd Xaa is Lys or is removed;

<220>

<221>misc_feature

<222>(24)..(24)

＜223〉the 24th Xaa is Tyr or Cys;

<220>

<221>misc_feature

<222>(26)..(26)

＜223〉the 26th Xaa is Tyr or Phe;

<220>

<221>misc_feature

<222>(28)..(28)

＜223〉the 28th Xaa is Asp or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

＜223〉the 29th Xaa is Glu or Val;

<220>

<221>misc_feature

<222>(30)..(30)

＜223〉the 30th Xaa is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(33)..(33)

＜223〉the 33rd Xaa is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(34)..(34)

＜223〉the 34th Xaa is Arg or Ser;

<220>

<221>misc_feature

<222>(36)..(36)

＜223〉the 36th Xaa is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(39)..(39)

＜223〉the 39th Xaa is Asn or Gly or is removed;

<220>

<221>misc_feature

<222>(40)..(40)

＜223〉the 40th Xaa is Tyr or Phe or is removed;

<220>

<221>misc_feature

<222>(42)..(42)

＜223〉the 42nd Xaa is Leu or Trp or is removed;

<220>

<221>misc_feature

<222>(44)..(44)

＜223〉the 44th Xaa is Ile or Leu or is removed;

<220>

<221>misc_feature

<222>(46)..(46)

＜223〉the 46th Xaa is Leu, Phe, Ile or Ser or be removed;

<220>

<221>misc_feature

<222>(48)..(48)

＜223〉the 48th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(49)..(49)

＜223〉the 49th Xaa is Leu or Phe or is removed;

<220>

<221>misc_feature

<222>(50)..(50)

＜223〉the 50th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(53)..(53)

＜223〉the 53rd Xaa is Gly or Leu or is removed;

<220>

<221>misc_feature

<222>(54)..(54)

＜223〉the 54th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(57)..(57)

＜223〉the 57th Xaa is Leu, Phe or Ile or be removed;

<220>

<221>misc_feature

<222>(62)..(62)

＜223〉the 62nd Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(63)..(63)

＜223〉the 63rd Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(64)..(64)

＜223〉the 64th Xaa is Gln or Cys or is removed;

<220>

<221>misc_feature

<222>(65)..(65)

＜223〉the 65th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(66)..(66)

＜223〉the 66th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(67)..(67)

＜223〉the 67th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(78)..(78)

＜223〉the 78th Xaa is Thr, Val or Ile or be removed;

<220>

<221>misc_feature

<222>(82)..(82)

＜223〉the 82nd Xaa is Ile, Val, Leu or Ala or be removed;

<220>

<221>misc_feature

<222>(87)..(87)

＜223〉the 87th Xaa is Met, Thr, Ile or Ala or be removed;

<220>

<221>misc_feature

<222>(90)..(90)

＜223〉the 90th Xaa is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(91)..(91)

＜223〉the 91st Xaa is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(92)..(92)

＜223〉the 92nd Xaa is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(93)..(93)

＜223〉the 93rd Xaa is Gly or Ser;

<220>

<221>misc_feature

<222>(94)..(94)

＜223〉the 94th Xaa is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(97)..(97)

＜223〉the 97th Xaa is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(98)..(98)

＜223〉the 98th Xaa is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(99)..(99)

＜223〉the 99th Xaa is Lys or Arg;

<220>

<221>misc_feature

<222>(102)..(102)

＜223〉the 102nd Xaa is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(103)..(103)

＜223〉the 103rd Xaa is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(105)..(105)

＜223〉the 105th Xaa is Ser, Phe or Leu or removal Leu;

<220>

<221>misc_feature

<222>(106)..(106)

＜223〉the 106th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(107)..(107)

＜223〉the 107th Xaa is Thr, Ser or Gly or be removed;

<220>

<221>misc_feature

<222>(112)..(112)

＜223〉the 112nd Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(113)..(113)

＜223〉the 113rd Xaa is Met or Leu or is removed;

<220>

<221>misc_feature

<222>(116)..(116)

＜223〉the 116th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(121)..(121)

＜223〉the 121st Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(123)..(123)

＜223〉the 123rd Xaa is Asn or Lys or is removed;

<400>25

Phe Xaa Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val

1 5 10 15

Xaa Pro Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp

20 25 30

Xaa Xaa Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa

35 40 45

Xaa Xaa Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa

50 55 60

Xaa Xaa Xaa Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu

65 70 75 80

Val Xaa Phe Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg

85 90 95

Xaa Xaa Xaa Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa

100 105 110

Xaa Val Ala Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

115 120

<210>26

<211>205

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

＜223〉the 2nd Xaa is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(5)..(5)

＜223〉the 5th Xaa is Leu, Ala or Met or be removed;

<220>

<221>misc_feature

<222>(9)..(9)

＜223〉the 9th Xaa is Ala or Gly or is removed;

<220>

<221>misc_feature

<222>(12)..(12)

＜223〉the 12nd Xaa is Ile, Val or Met or be removed;

<220>

<221>misc_feature

<222>(14)..(14)

＜223〉the 14th Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(15)..(15)

＜223〉the 15th Xaa is Arg or Lys or is removed;

<220>

<221>misc_feature

<222>(16)..(16)

＜223〉the 16th Xaa is Ala or Ser or is removed;

<220>

<221>misc_feature

<222>(17)..(17)

＜223〉the 17th Xaa is Leu or Ser or is removed;

<220>

<221>misc_feature

<222>(19)..(19)

＜223〉the 19th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(20)..(20)

＜223〉the 20th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(21)..(21)

＜223〉the 21st Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(22)..(22)

＜223〉the 22nd Xaa is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(24)..(24)

＜223〉the 24th Xaa is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(25)..(25)

＜223〉the 25th Xaa is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(27)..(27)

＜223〉the 27th Xaa is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(28)..(28)

＜223〉the 28th Xaa is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

＜223〉the 29th Xaa is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(30)..(30)

＜223〉the 30th Xaa is Tyr or Asn;

<220>

<221>misc_feature

<222>(31)..(31)

＜223〉the 31st Xaa is Ser or Arg;

<220>

<221>misc_feature

<222>(32)..(32)

＜223〉the 32nd Xaa is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(33)..(33)

＜223〉the 33rd Xaa is Lys or Arg or skips;

<220>

<221>misc_feature

<222>(34)..(34)

＜223〉the 34th Xaa is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(35)..(35)

＜223〉the 35th Xaa is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(36)..(36)

＜223〉the 36th Xaa is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(37)..(37)

＜223〉the 37th Xaa is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(38)..(38)

＜223〉the 38th Xaa is His or Leu;

<220>

<221>misc_feature

<222>(39)..(39)

＜223〉the 39th Xaa is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(40)..(40)

＜223〉the 40th Xaa is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(41)..(41)

＜223〉the 41st Xaa is Asp or Ser;

<220>

<221>misc_feature

<222>(42)..(42)

＜223〉the 42nd Xaa is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(43)..(43)

＜223〉the 43rd Xaa is Arg or skips;

<220>

<221>misc_feature

<222>(44)..(44)

＜223〉the 44th Xaa is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(46)..(46)

＜223〉the 46th Xaa is Ser or Asp;

<220>

<221>misc_feature

<222>(47)..(47)

＜223〉the 47th Xaa is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(48)..(48)

＜223〉the 48th Xaa is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(49)..(49)

＜223〉the 49th Xaa is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(50)..(50)

＜223〉the 50th Xaa is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(51)..(51)

＜223〉the 51st Xaa is Leu, Ala, Thr or Val;

<220>

<221>misc_feature

<222>(52)..(52)

＜223〉the 52nd Xaa is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(53)..(53)

＜223〉the 53rd Xaa is Cys or is removed;

<220>

<221>misc_feature

<222>(54)..(54)

＜223〉the 54th Xaa is Arg or is removed;

<220>

<221>misc_feature

<222>(55)..(55)

＜223〉the 55th Xaa is Leu, Val, Ala or Ser or be removed;

<220>

<221>misc_feature

<222>(56)..(56)

＜223〉the 56th Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(57)..(57)

＜223〉the 57th Xaa is Phe, Ala, Thr or Met or be removed;

<220>

<221>misc_feature

<222>(58)..(58)

＜223〉the 58th Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(59)..(59)

＜223〉the 59th Xaa is Leu, Phe or Met or be removed;

<220>

<221>misc_feature

<222>(63)..(63)

＜223〉the 63rd Xaa is Cys, Gly or Ser or be removed;

<220>

<221>misc_feature

<222>(64)..(64)

＜223〉the 64th Xaa is Val, Ile or Met or be removed;

<220>

<221>misc_feature

<222>(65)..(65)

＜223〉the 65th Xaa is Ala, Val, Met or Ile or be removed;

<220>

<221>misc_feature

<222>(69)..(69)

＜223〉the 69th Xaa is Tyr or Cys or is removed;

<220>

<221>misc_feature

<222>(76)..(76)

＜223〉the 76th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(79)..(79)

<220>

<221>misc_feature

<222>(80)..(80)

<220>

<221>misc_feature

<222>(81)..(81)

<220>

<221>misc_feature

<222>(83)..(83)

＜223〉the 83rd Xaa is Arg or Ser or is removed;

<220>

<221>misc_feature

<222>(86)..(86)

＜223〉the 86th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(87)..(87)

＜223〉the 87th Xaa is Ser, Gly or Cys or be removed;

<220>

<221>misc_feature

<222>(92)..(92)

＜223〉the 92nd Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(94)..(94)

＜223〉the 94th Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(98)..(98)

＜223〉the 98th Xaa is Val, Leu or Ile or be removed;

<220>

<221>misc_feature

<222>(101)..(101)

＜223〉the 101st Xaa is Gly, Ala, Met or Val or be removed;

<220>

<221>misc_feature

<222>(102)..(102)

＜223〉the 102nd Xaa is Ile, Val, Thr or Ala or be removed;

<220>

<221>misc_feature

<222>(103)..(103)

＜223〉the 103rd Xaa is Val or is removed;

<220>

<221>misc_feature

<222>(104)..(104)

＜223〉the 104th Xaa is Lys or is removed;

<220>

<221>misc_feature

<222>(105)..(105)

＜223〉the 105th Xaa is Tyr or Cys;

<220>

<221>misc_feature

<222>(107)..(107)

＜223〉the 107th Xaa is Tyr or Phe;

<220>

<221>misc_feature

<222>(109)..(109)

＜223〉the 109th Xaa is Asp or Asn;

<220>

<221>misc_feature

<222>(110)..(110)

＜223〉the 110th Xaa is Glu or Val;

<220>

<221>misc_feature

<222>(111)..(111)

＜223〉the 111st Xaa is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(114)..(114)

＜223〉the 114th Xaa is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(115)..(115)

＜223〉the 115th Xaa is Arg or Ser;

<220>

<221>misc_feature

<222>(117)..(117)

＜223〉the 117th Xaa is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(120)..(120)

＜223〉the 120th Xaa is Asn or Gly or is removed;

<220>

<221>misc_feature

<222>(121)..(121)

＜223〉the 121st Xaa is Tyr or Phe or is removed;

<220>

<221>misc_feature

<222>(123)..(123)

＜223〉the 123rd Xaa is Leu or Trp or is removed;

<220>

<221>misc_feature

<222>(125)..(125)

＜223〉the 125th Xaa is Ile or Leu or is removed;

<220>

<221>misc_feature

<222>(127)..(127)

＜223〉the 127th Xaa is Leu, Phe, Ile or Ser or be removed;

<220>

<221>misc_feature

<222>(129)..(129)

＜223〉the 129th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

＜223〉the 130th Xaa is Leu or Phe or is removed;

<220>

<221>misc_feature

<222>(131)..(131)

＜223〉the 131st Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(134)..(134)

＜223〉the 134th Xaa is Gly or Leu or is removed;

<220>

<221>misc_feature

<222>(135)..(135)

＜223〉the 135th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(138)..(138)

＜223〉the 138th Xaa is Leu, Phe or Ile or be removed;

<220>

<221>misc_feature

<222>(143)..(143)

＜223〉the 143rd Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(144)..(144)

＜223〉the 144th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(145)..(145)

＜223〉the 145th Xaa is Gln or Cys or is removed;

<220>

<221>misc_feature

<222>(146)..(146)

＜223〉the 146th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(147)..(147)

＜223〉the 147th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(148)..(148)

＜223〉the 148th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(159)..(159)

＜223〉the 159th Xaa is Thr, Val or Ile or be removed;

<220>

<221>misc_feature

<222>(163)..(163)

＜223〉the 163rd Xaa is Ile, Val, Leu or Ala or be removed;

<220>

<221>misc_feature

<222>(168)..(168)

＜223〉the 168th Xaa is Met, Thr, Ile or Ala or be removed;

<220>

<221>misc_feature

<222>(171)..(171)

＜223〉the 171st Xaa is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(172)..(172)

＜223〉the 172nd Xaa is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(173)..(173)

＜223〉the 173rd Xaa is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(174)..(174)

＜223〉the 174th Xaa is Gly or Ser;

<220>

<221>misc_feature

<222>(175)..(175)

＜223〉the 175th Xaa is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(178)..(178)

＜223〉the 178th Xaa is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(179)..(179)

＜223〉the 179th Xaa is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(180)..(180)

＜223〉the 180th Xaa is Lys or Arg;

<220>

<221>misc_feature

<222>(183)..(183)

＜223〉the 183rd Xaa is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(184)..(184)

＜223〉the 184th Xaa is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(186)..(186)

＜223〉the 186th Xaa is Ser, Phe or Leu or removal Leu;

<220>

<221>misc_feature

<222>(187)..(187)

＜223〉the 187th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(188)..(188)

＜223〉the 188th Xaa is Thr, Ser or Gly or be removed;

<220>

<221>misc_feature

<222>(193)..(193)

＜223〉the 193rd Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(194)..(194)

＜223〉the 194th Xaa is Met or Leu or is removed;

<220>

<221>misc_feature

<222>(197)..(197)

＜223〉the 197th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(202)..(202)

＜223〉the 202nd Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(204)..(204)

＜223〉the 204th Xaa is Asn or Lys or is removed;

<400>26

Asn Xaa Ile His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa

1 5 10 15

Xaa Ser Xaa Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

20 25 30

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa

35 40 45

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa

50 55 60

Xaa Ala Asn Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa

65 70 75 80

Xaa Phe Xaa Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe

85 90 95

Val Xaa Pro Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys

100 105 110

Trp Xaa Xaa Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro

115 120 125

Xaa Xaa Xaa Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa

130 135 140

Xaa Xaa Xaa Xaa Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His

145 150 155 160

Glu Val Xaa Phe Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu

165 170 175

Arg Xaa Xaa Xaa Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly

180 185 190

Xaa Xaa Val Ala Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

195 200 205

<210>27

<211>203

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

＜223〉the 123rd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(124)..(124)

＜223〉the 124th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(125)..(125)

＜223〉the 125th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(127)..(127)

＜223〉the 127th Xaa is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

＜223〉the 130th Xaa is Leu, Ala or Met or be removed;

<220>

<221>misc_feature

<222>(134)..(134)

＜223〉the 134th Xaa is Ala or Gly or is removed;

<220>

<221>misc_feature

<222>(137)..(137)

＜223〉the 137th Xaa is Ile, Val or Met or be removed;

<220>

<221>misc_feature

<222>(139)..(139)

＜223〉the 139th Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(140)..(140)

＜223〉the 140th Xaa is Arg or Lys or is removed;

<220>

<221>misc_feature

<222>(141)..(141)

＜223〉the 141st Xaa is Ala or Ser or is removed;

<220>

<221>misc_feature

<222>(142)..(142)

＜223〉the 142nd Xaa is Leu or Ser or is removed;

<220>

<221>misc_feature

<222>(144)..(144)

＜223〉the 144th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(145)..(145)

＜223〉the 145th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(146)..(146)

＜223〉the 146th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(147)..(147)

＜223〉the 147th Xaa is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(149)..(149)

＜223〉the 149th Xaa is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(150)..(150)

＜223〉the 150th Xaa is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(152)..(152)

＜223〉the 152nd Xaa is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(153)..(153)

＜223〉the 153rd Xaa is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

＜223〉the 154th Xaa is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(155)..(155)

＜223〉the 155th Xaa is Tyr or Asn;

<220>

<221>misc_feature

<222>(156)..(156)

＜223〉the 156th Xaa is Ser or Arg;

<220>

<221>misc_feature

<222>(157)..(157)

＜223〉the 157th Xaa is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(158)..(158)

＜223〉the 158th Xaa is Lys or Arg or skips;

<220>

<221>misc_feature

<222>(159)..(159)

＜223〉the 159th Xaa is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(160)..(160)

＜223〉the 160th Xaa is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(161)..(161)

＜223〉the 161st Xaa is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(162)..(162)

＜223〉the 162nd Xaa is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(163)..(163)

＜223〉the 163rd Xaa is His or Leu;

<220>

<221>misc_feature

<222>(164)..(164)

＜223〉the 164th Xaa is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(165)..(165)

＜223〉the 165th Xaa is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(166)..(166)

＜223〉the 166th Xaa is Asp or Ser;

<220>

<221>misc_feature

<222>(167)..(167)

＜223〉the 167th Xaa is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(168)..(168)

＜223〉the 168th Xaa is Arg or skips;

<220>

<221>misc_feature

<222>(169)..(169)

＜223〉the 169th Xaa is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(171)..(171)

＜223〉the 171st Xaa is Ser or Asp;

<220>

<221>misc_feature

<222>(172)..(172)

＜223〉the 172nd Xaa is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(173)..(173)

＜223〉the 173rd Xaa is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(174)..(174)

＜223〉the 174th Xaa is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(175)..(175)

＜223〉the 175th Xaa is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(176)..(176)

＜223〉the 176th Xaa is Leu, Ala, Thr or Val;

<220>

<221>misc_feature

<222>(177)..(177)

＜223〉the 177th Xaa is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(178)..(178)

＜223〉the 178th Xaa is Cys or is removed;

<220>

<221>misc_feature

<222>(179)..(179)

＜223〉the 179th Xaa is Arg or is removed;

<220>

<221>misc_feature

<222>(180)..(180)

＜223〉the 180th Xaa is Leu, Val, Ala or Ser or be removed;

<220>

<221>misc_feature

<222>(181)..(181)

＜223〉the 181st Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(182)..(182)

＜223〉the 182nd Xaa is Phe, Ala, Thr or Met or be removed;

<220>

<221>misc_feature

<222>(183)..(183)

＜223〉the 183rd Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(184)..(184)

＜223〉the 184th Xaa is Leu, Phe or Met or be removed;

<220>

<221>misc_feature

<222>(188)..(188)

＜223〉the 188th Xaa is Cys, Gly or Ser or be removed;

<220>

<221>misc_feature

<222>(189)..(189)

＜223〉the 189th Xaa is Val, Ile or Met or be removed;

<220>

<221>misc_feature

<222>(190)..(190)

＜223〉the 190th Xaa is Ala, Val, Met or Ile or be removed;

<220>

<221>misc_feature

<222>(194)..(194)

＜223〉the 194th Xaa is Tyr or Cys or is removed;

<220>

<221>misc_feature

<222>(201)..(201)

＜223〉the 102nd Xaa is Val or Leu or is removed;

<400>27

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser Leu Pro

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Asn Xaa Ile

115 120 125

His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa Xaa Ser Xaa

130 135 140

Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

145 150 155 160

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

165 170 175

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa Xaa Ala Asn

180 185 190

Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu

195 200

<210>28

<211>189

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(127)..(127)

＜223〉the 127th Xaa is Arg or Ser or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

＜223〉the 130th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(131)..(131)

＜223〉the 131st Xaa is Ser, Gly or Cys or be removed;

<220>

<221>misc_feature

<222>(136)..(136)

＜223〉the 136th Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(138)..(138)

＜223〉the 138th Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(142)..(142)

＜223〉the 142nd Xaa is Val, Leu or Ile or be removed;

<220>

<221>misc_feature

<222>(145)..(145)

＜223〉the 145th Xaa is Gly, Ala, Met or Val or be removed;

<220>

<221>misc_feature

<222>(146)..(146)

＜223〉the 146th Xaa is Ile, Val, Thr or Ala or be removed;

<220>

<221>misc_feature

<222>(147)..(147)

＜223〉the 147th Xaa is Val or is removed;

<220>

<221>misc_feature

<222>(148)..(148)

＜223〉the 148th Xaa is Lys or is removed;

<220>

<221>misc_feature

<222>(149)..(149)

＜223〉the 149th Xaa is Tyr or Cys;

<220>

<221>misc_feature

<222>(151)..(151)

＜223〉the 151st Xaa is Tyr or Phe;

<220>

<221>misc_feature

<222>(153)..(153)

＜223〉the 153rd Xaa is Asp or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

＜223〉the 154th Xaa is Glu or Val;

<220>

<221>misc_feature

<222>(155)..(155)

＜223〉the 155th Xaa is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(158)..(158)

＜223〉the 158th Xaa is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(159)..(159)

＜223〉the 159th Xaa is Arg or Ser;

<220>

<221>misc_feature

<222>(161)..(161)

＜223〉the 161st Xaa is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(164)..(164)

＜223〉the 164th Xaa is Asn or Gly or is removed;

<220>

<221>misc_feature

<222>(165)..(165)

＜223〉the 165th Xaa is Tyr or Phe or is removed;

<220>

<221>misc_feature

<222>(167)..(167)

＜223〉the 167th Xaa is Leu or Trp or is removed;

<220>

<221>misc_feature

<222>(169)..(169)

＜223〉the 169th Xaa is Ile or Leu or is removed;

<220>

<221>misc_feature

<222>(171)..(171)

＜223〉the 171st Xaa is Leu, Phe, Ile or Ser or be removed;

<220>

<221>misc_feature

<222>(173)..(173)

＜223〉the 173rd Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(174)..(174)

＜223〉the 174th Xaa is Leu or Phe or is removed;

<220>

<221>misc_feature

<222>(175)..(175)

＜223〉the 175th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(178)..(178)

＜223〉the 178th Xaa is Gly or Leu or is removed;

<220>

<221>misc_feature

<222>(179)..(179)

＜223〉the 179th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(182)..(182)

＜223〉the 182nd Xaa is Leu, Phe or Ile or be removed;

<220>

<221>misc_feature

<222>(187)..(187)

＜223〉the 187th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(188)..(188)

＜223〉the 188th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(189)..(189)

＜223〉the 189th Xaa is Gln or Cys or is removed;

<400>28

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

ro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser Leu Pro

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Phe Xaa Leu

115 120 125

Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val Xaa Pro Trp

130 135 140

Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp Xaa Xaa Asn

145 150 155 160

Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa Xaa Xaa Ala

165 170 175

Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa

180 185

<210>29

<211>182

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(136)..(136)

＜223〉the 136th Xaa is Thr, Val or Ile or be removed;

<220>

<221>misc_feature

<222>(140)..(140)

＜223〉the 140th Xaa is Ile, Val, Leu or Ala or be removed;

<220>

<221>misc_feature

<222>(145)..(145)

＜223〉the 145th Xaa is Met, Thr, Ile or Ala or be removed;

<220>

<221>misc_feature

<222>(148)..(148)

＜223〉the 148th Xaa is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(149)..(149)

＜223〉the 149th Xaa is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(150)..(150)

＜223〉the 150th Xaa is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(151)..(151)

＜223〉the 151st Xaa is Gly or Ser;

<220>

<221>misc_feature

<222>(152)..(152)

＜223〉the 152nd Xaa is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(155)..(155)

＜223〉the 155th Xaa is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(156)..(156)

＜223〉the 156th Xaa is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(157)..(157)

＜223〉the 157th Xaa is Lys or Arg;

<220>

<221>misc_feature

<222>(160)..(160)

＜223〉the 160th Xaa is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(161)..(161)

＜223〉the 161st Xaa is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(163)..(163)

＜223〉the 163rd Xaa is Ser, Phe or Leu or removal Leu;

<220>

<221>misc_feature

<222>(164)..(164)

＜223〉the 164th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(165)..(165)

＜223〉the 165th Xaa is Thr, Ser or Gly or be removed;

<220>

<221>misc_feature

<222>(170)..(170)

＜223〉the 170th Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(171)..(171)

＜223〉the 171st Xaa is Met or Leu or is removed;

<220>

<221>misc_feature

<222>(174)..(174)

＜223〉the 174th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(179)..(179)

＜223〉the 179th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(181)..(181)

＜223〉the 181st Xaa is Asn or Lys or is removed;

<400>29

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser Leu Pro

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Ser Thr Leu

115 120 125

Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa Phe Ala Phe Val

130 135 140

Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg Xaa Xaa Xaa Leu Phe Xaa

145 150 155 160

Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val Ala Xaa Leu Tyr

165 170 175

Cys Phe Xaa Asn Xaa Glu

180

<210>30

<211>270

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(127)..(127)

＜223〉the 127th Xaa is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

＜223〉the 130th Xaa is Leu, Ala or Met or be removed;

<220>

<221>misc_feature

<222>(134)..(134)

＜223〉the 134th Xaa is Ala or Gly or is removed;

<220>

<221>misc_feature

<222>(137)..(137)

＜223〉the 137th Xaa is Ile, Val or Met or be removed;

<220>

<221>misc_feature

<222>(139)..(139)

＜223〉the 139th Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(140)..(140)

＜223〉the 140th Xaa is Arg or Lys or is removed;

<220>

<221>misc_feature

<222>(141)..(141)

＜223〉the 141st Xaa is Ala or Ser or is removed;

<220>

<221>misc_feature

<222>(142)..(142)

＜223〉the 142nd Xaa is Leu or Ser or is removed;

<220>

<221>misc_feature

<222>(144)..(144)

＜223〉the 144th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(145)..(145)

＜223〉the 145th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(146)..(146)

＜223〉the 146th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(147)..(147)

＜223〉the 147th Xaa is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(149)..(149)

＜223〉the 149th Xaa is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(150)..(150)

＜223〉the 150th Xaa is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(152)..(152)

＜223〉the 152nd Xaa is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(153)..(153)

＜223〉the 153rd Xaa is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

＜223〉the 154th Xaa is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(155)..(155)

＜223〉the 155th Xaa is Tyr or Asn;

<220>

<221>misc_feature

<222>(156)..(156)

＜223〉the 156th Xaa is Ser or Arg;

<220>

<221>misc_feature

<222>(157)..(157)

＜223〉the 157th Xaa is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(158)..(158)

＜223〉the 158th Xaa is Lys or Arg or skips;

<220>

<221>misc_feature

<222>(159)..(159)

＜223〉the 159th Xaa is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(160)..(160)

＜223〉the 160th Xaa is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(161)..(161)

＜223〉the 161st Xaa is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(162)..(162)

＜223〉the 162nd Xaa is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(163)..(163)

＜223〉the 163rd Xaa is His or Leu;

<220>

<221>misc_feature

<222>(164)..(164)

＜223〉the 164th Xaa is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(165)..(165)

＜223〉the 165th Xaa is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(166)..(166)

＜223〉the 166th Xaa is Asp or Ser;

<220>

<221>misc_feature

<222>(167)..(167)

＜223〉the 167th Xaa is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(168)..(168)

＜223〉the 168th Xaa is Arg or skips;

<220>

<221>misc_feature

<222>(169)..(169)

＜223〉the 169th Xaa is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(171)..(171)

＜223〉the 171st Xaa is Ser or Asp;

<220>

<221>misc_feature

<222>(172)..(172)

＜223〉the 172nd Xaa is Tyr, Asp or Thr

<220>

<221>misc_feature

<222>(173)..(173)

＜223〉the 173rd Xaa is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(174)..(174)

＜223〉the 174th Xaa is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(175)..(175)

＜223〉the 175th Xaa is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(176)..(176)

＜223〉the 176th Xaa is Leu, Ala, Thr or Val;

<220>

<221>misc_feature

<222>(177)..(177)

＜223〉the 177th Xaa is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(178)..(178)

＜223〉the 178th Xaa is Cys or is removed;

<220>

<221>misc_feature

<222>(179)..(179)

＜223〉the 179th Xaa is Arg or is removed;

<220>

<221>misc_feature

<222>(180)..(180)

＜223〉the 180th Xaa is Leu, Val, Ala or Ser or be removed;

<220>

<221>misc_feature

<222>(181)..(181)

＜223〉the 181st Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(182)..(182)

＜223〉the 182nd Xaa is Phe, Ala, Thr or Met or be removed;

<220>

<221>misc_feature

<222>(183)..(183)

＜223〉the 183rd Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(184)..(184)

＜223〉the 184th Xaa is Leu, Phe or Met or be removed;

<220>

<221>misc_feature

<222>(188)..(188)

＜223〉the 188th Xaa is Cys, Gly or Ser or be removed;

<220>

<221>misc_feature

<222>(189)..(189)

＜223〉the 189th Xaa is Val, Ile or Met or be removed;

<220>

<221>misc_feature

<222>(190)..(190)

＜223〉the 190th Xaa is Ala, Val, Met or Ile or be removed;

<220>

<221>misc_feature

<222>(194)..(194)

＜223〉the 194th Xaa is Tyr or Cys or is removed;

<220>

<221>misc_feature

<222>(201)..(201)

＜223〉the 201st Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(204)..(204)

＜223〉the 204th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(205)..(205)

＜223〉the 205th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(206)..(206)

＜223〉the 206th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(208)..(208)

＜223〉the 208th Xaa is Arg or Ser or is removed;

<220>

<221>misc_feature

<222>(211)..(211)

＜223〉the 211st Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(212)..(212)

＜223〉the 212nd Xaa is Ser, Gly or Cys or be removed;

<220>

<221>misc_feature

<222>(217)..(217)

＜223〉the 217th Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(219)..(219)

＜223〉the 219th Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(223)..(223)

＜223〉the 223rd Xaa is Val, Leu or Ile or be removed;

<220>

<221>misc_feature

<222>(226)..(226)

＜223〉the 226th Xaa is Gly, Ala, Met or Val or be removed;

<220>

<221>misc_feature

<222>(227)..(227)

＜223〉the 227th Xaa is Ile, Val, Thr or Ala or be removed;

<220>

<221>misc_feature

<222>(228)..(228)

＜223〉the 228th Xaa is Val or is removed;

<220>

<221>misc_feature

<222>(229)..(229)

＜223〉the 229th Xaa is Lys or is removed;

<220>

<221>misc_feature

<222>(230)..(230)

＜223〉the 230th Xaa is Tyr or Cys;

<220>

<221>misc_feature

<222>(232)..(232)

＜223〉the 232nd Xaa is Tyr or Phe;

<220>

<221>misc_feature

<222>(234)..(234)

＜223〉the 234th Xaa is Asp or Asn;

<220>

<221>misc_feature

<222>(235)..(235)

＜223〉the 235th Xaa is Glu or Val;

<220>

<221>misc_feature

<222>(236)..(236)

＜223〉the 236th Xaa is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(239)..(239)

＜223〉the 239th Xaa is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(240)..(240)

＜223〉the 240th Xaa is Arg or Ser;

<220>

<221>misc_feature

<222>(242)..(242)

＜223〉the 242nd Xaa is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(245)..(245)

＜223〉the 245th Xaa is Asn or Gly or is removed;

<220>

<221>misc_feature

<222>(246)..(246)

＜223〉the 246th Xaa is Tyr or Phe or is removed;

<220>

<221>misc_feature

<222>(248)..(248)

＜223〉the 248th Xaa is Leu or Trp or is removed;

<220>

<221>misc_feature

<222>(250)..(250)

＜223〉the 250th Xaa is Ile or Leu or is removed;

<220>

<221>misc_feature

<222>(252)..(252)

＜223〉the 252nd Xaa is Leu, Phe, Ile or Ser or be removed;

<220>

<221>misc_feature

<222>(254)..(254)

＜223〉the 254th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(255)..(255)

＜223〉the 255th Xaa is Leu or Phe or is removed;

<220>

<221>misc_feature

<222>(256)..(256)

＜223〉the 256th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(259)..(259)

＜223〉the 259th Xaa is Gly or Leu or is removed;

<220>

<221>misc_feature

<222>(260)..(260)

＜223〉the 260th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(263)..(263)

＜223〉the 263rd Xaa is Leu, Phe or Ile or be removed;

<220>

<221>misc_feature

<222>(268)..(268)

＜223〉the 268th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(269)..(269)

＜223〉the 269th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(270)..(270)

＜223〉the 270th Xaa is Gln or Cys or is removed;

<400>30

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser Leu Pro

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Asn Xaa Ile

115 120 125

His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa Xaa Ser Xaa

130 135 140

Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

145 150 155 160

aa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

165 170 175

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa Xaa Ala Asn

180 185 190

Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa Xaa Phe Xaa

195 200 205

Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val Xaa Pro

210 215 220

Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp Xaa Xaa

225 230 235 240

Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa Xaa Xaa

245 250 255

Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa

260 265 270

<210>31

<211>263

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(127)..(127)

＜223〉the 127th Xaa is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

＜223〉the 130th Xaa is Leu, Ala or Met or be removed;

<220>

<221>misc_feature

<222>(134)..(134)

＜223〉the 134th Xaa is Ala or Gly or is removed;

<220>

<221>misc_feature

<222>(137)..(137)

＜223〉the 137th Xaa is Ile, Val or Met or be removed;

<220>

<221>misc_feature

<222>(139)..(139)

＜223〉the 139th Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(140)..(140)

＜223〉the 140th Xaa is Arg or Lys or is removed;

<220>

<221>misc_feature

<222>(141)..(141)

＜223〉the 141st Xaa is Ala or Ser or is removed;

<220>

<221>misc_feature

<222>(142)..(142)

＜223〉the 142nd Xaa is Leu or Ser or is removed;

<220>

<221>misc_feature

<222>(144)..(144)

＜223〉the 144th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(145)..(145)

＜223〉the 145th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(146)..(146)

＜223〉the 146th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(147)..(147)

＜223〉the 147th Xaa is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(149)..(149)

＜223〉the 149th Xaa is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(150)..(150)

＜223〉the 150th Xaa is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(152)..(152)

＜223〉the 152nd Xaa is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(153)..(153)

＜223〉the 153rd Xaa is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

＜223〉the 154th Xaa is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(155)..(155)

＜223〉the 155th Xaa is Tyr or Asn;

<220>

<221>misc_feature

<222>(156)..(156)

＜223〉the 156th Xaa is Ser or Arg;

<220>

<221>misc_feature

<222>(157)..(157)

＜223〉the 157th Xaa is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(158)..(158)

＜223〉the 158th Xaa is Lys or Arg or skips;

<220>

<221>misc_feature

<222>(159)..(159)

＜223〉the 159th Xaa is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(160)..(160)

＜223〉the 160th Xaa is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(161)..(161)

＜223〉the 161st Xaa is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(162)..(162)

＜223〉the 162nd Xaa is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(163)..(163)

＜223〉the 163rd Xaa is His or Leu;

<220>

<221>misc_feature

<222>(164)..(164)

＜223〉the 164th Xaa is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(165)..(165)

＜223〉the 165th Xaa is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(166)..(166)

＜223〉the 166th Xaa is Asp or Ser;

<220>

<221>misc_feature

<222>(167)..(167)

＜223〉the 167th Xaa is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(168)..(168)

＜223〉the 168th Xaa is Arg or skips;

<220>

<221>misc_feature

<222>(169)..(169)

＜223〉the 169th Xaa is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(171)..(171)

＜223〉the 171st Xaa is Ser or Asp;

<220>

<221>misc_feature

<222>(172)..(172)

＜223〉the 172nd Xaa is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(173)..(173)

＜223〉the 173rd Xaa is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(174)..(174)

＜223〉the 174th Xaa is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(175)..(175)

＜223〉the 175th Xaa is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(176)..(176)

＜223〉the 176th Xaa is Leu, Ala, Thr or Val;

<220>

<221>misc_feature

<222>(177)..(177)

＜223〉the 177th Xaa is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(178)..(178)

＜223〉the 178th Xaa is Cys or is removed;

<220>

<221>misc_feature

<222>(179)..(179)

＜223〉the 179th Xaa is Arg or is removed;

<220>

<221>misc_feature

<222>(180)..(180)

＜223〉the 180th Xaa is Leu, Val, Ala or Ser or be removed;

<220>

<221>misc_feature

<222>(181)..(181)

＜223〉the 181st Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(182)..(182)

＜223〉the 182nd Xaa is Phe, Ala, Thr or Met or be removed;

<220>

<221>misc_feature

<222>(183)..(183)

＜223〉the 183rd Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(184)..(184)

＜223〉the 184th Xaa is Leu, Phe or Met or be removed;

<220>

<221>misc_feature

<222>(188)..(188)

＜223〉the 188th Xaa is Cys, Gly or Ser or be removed;

<220>

<221>misc_feature

<222>(189)..(189)

＜223〉the 189th Xaa is Val, Ile or Met or be removed;

<220>

<22l>misc_feature

<222>(190)..(190)

＜223〉the 190th Xaa is Ala, Val, Met or Ile or be removed;

<220>

<221>misc_feature

<222>(194)..(194)

＜223〉the 194th Xaa is Tyr or Cys or is removed;

<220>

<221>misc_feature

<222>(201)..(201)

＜223〉the 201st Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(204)..(204)

<220>

<221>misc_feature

<222>(205)..(205)

<220>

<221>misc_feature

<222>(206)..(206)

<220>

<221>misc_feature

<222>(217)..(217)

＜223〉the 217th Xaa is Thr, Val or Ile or be removed;

<220>

<221>misc_feature

<222>(221)..(221)

＜223〉the 221st Xaa is Ile, Val, Leu or Ala or be removed;

<220>

<221>misc_feature

<222>(226)..(226)

＜223〉the 226th Xaa is Met, Thr, Ile or Ala or be removed;

<220>

<221>misc_feature

<222>(229)..(229)

＜223〉the 229th Xaa is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(230)..(230)

＜223〉the 230th Xaa is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(231)..(231)

＜223〉the 231st Xaa is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(232)..(232)

＜223〉the 232nd Xaa is Gly or Ser;

<220>

<221>misc_feature

<222>(233)..(233)

＜223〉the 233rd Xaa is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(236)..(236)

＜223〉the 236th Xaa is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(237)..(237)

＜223〉the 237th Xaa is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(238)..(238)

＜223〉the 238th Xaa is Lys or Arg;

<220>

<221>misc_feature

<222>(241)..(241)

＜223〉the 241st Xaa is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(242)..(242)

＜223〉the 242nd Xaa is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(244)..(244)

＜223〉the 244th Xaa is Ser, Phe or Leu or removal Leu;

<220>

<221>misc_feature

<222>(245)..(245)

＜223〉the 245th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(246)..(246)

＜223〉the 246th Xaa is Thr, Ser or Gly or be removed;

<220>

<221>misc_feature

<222>(251)..(251)

＜223〉the 251st Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(252)..(252)

＜223〉the 252nd Xaa is Met or Leu or is removed;

<220>

<221>misc_feature

<222>(255)..(255)

＜223〉the 255th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(260)..(260)

＜223〉the 260th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(262)..(262)

＜223〉the 262nd Xaa is Asn or Lys or is removed;

<400>31

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

ys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser Leu Pro

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Asn Xaa Ile

115 120 125

His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa Xaa Ser Xaa

130 135 140

Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

145 150 155 160

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

165 170 175

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa Xaa Ala Asn

180 185 190

Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa Xaa Ser Thr

195 200 205

Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa Phe Ala Phe

210 215 220

Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg Xaa Xaa Xaa Leu Phe

225 230 235 240

Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val Ala Xaa Leu

245 250 255

Tyr Cys Phe Xaa Asn Xaa Glu

260

<210>32

<211>249

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

＜223〉the 123rd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or 61y Gly Gly GlySer;

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(127)..(127)

＜223〉the 127th Xaa is Arg or Ser or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

＜223〉the 130th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(131)..(131)

＜223〉the 131st Xaa is Ser, Gly or Cys or be removed;

<220>

<221>misc_feature

<222>(136)..(136)

＜223〉the 136th Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(138)..(138)

＜223〉the 138th Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(142)..(142)

＜223〉the 142nd Xaa is Val, Leu or Ile or be removed;

<220>

<221>misc_feature

<222>(145)..(145)

＜223〉the 145th Xaa is Gly, Ala, Met or Val or be removed;

<220>

<221>misc_feature

<222>(146)..(146)

＜223〉the 146th Xaa is Ile, Val, Thr or Ala or be removed;

<220>

<221>misc_feature

<222>(147)..(147)

＜223〉the 147th Xaa is Val or is removed;

<220>

<221>misc_feature

<222>(148)..(148)

＜223〉the 148th Xaa is Lys or is removed;

<220>

<221>misc_feature

<222>(149)..(149)

＜223〉the 149th Xaa is Tyr or Cys;

<220>

<221>misc_feature

<222>(151)..(151)

＜223〉the 151st Xaa is Tyr or Phe;

<220>

<221>misc_feature

<222>(153)..(153)

＜223〉the 153rd Xaa is Asp or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

＜223〉the 154th Xaa is Glu or Val;

<220>

<221>misc_feature

<222>(155)..(155)

＜223〉the 155th Xaa is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(158)..(158)

＜223〉the 158th Xaa is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(159)..(159)

＜223〉the 159th Xaa is Arg or Ser;

<220>

<221>misc_feature

<222>(161)..(161)

＜223〉the 161st Xaa is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(164)..(164)

＜223〉the 164th Xaa is Asn or Gly or is removed;

<220>

<221>misc_feature

<222>(165)..(165)

＜223〉the 165th Xaa is Tyr or Phe or is removed;

<220>

<221>misc_feature

<222>(167)..(167)

＜223〉the 167th Xaa is Leu or Trp or is removed;

<220>

<221>misc_feature

<222>(169)..(169)

＜223〉the 169th Xaa is Ile or Leu or is removed;

<220>

<221>misc_feature

<222>(171)..(171)

＜223〉the 171st Xaa is Leu, Phe, Ile or Ser or be removed;

<220>

<221>misc_feature

<222>(173)..(173)

＜223〉the 173rd Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(174)..(174)

＜223〉the 174th Xaa is Leu or Phe or is removed;

<220>

<221>misc_feature

<222>(175)..(175)

＜223〉the 175th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(178)..(178)

＜223〉the 178th Xaa is Gly or Leu or is removed;

<220>

<221>misc_feature

<222>(179)..(179)

＜223〉the 179th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(182)..(182)

＜223〉the 182nd Xaa is Leu, Phe or Ile or be removed;

<220>

<221>misc_feature

<222>(187)..(187)

＜223〉the 187th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(188)..(188)

＜223〉the 188th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(189)..(189)

＜223〉the 189th Xaa is Gln or Cys or is removed;

<220>

<221>misc_feature

<222>(190)..(190)

＜223〉the 190th Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(191)..(191)

＜223〉the 191st Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(192)..(192)

＜223〉the 192nd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(203)..(203)

＜223〉the 203rd Xaa is Thr, Val or Ile or be removed;

<220>

<221>misc_feature

<222>(207)..(207)

＜223〉the 207th Xaa is Ile, Val, Leu or Ala or be removed;

<220>

<221>misc_feature

<222>(212)..(212)

＜223〉the 212nd Xaa is Met, Thr, Ile or Ala or be removed;

<220>

<221>misc_feature

<222>(215)..(215)

＜223〉the 215th Xaa is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(216)..(216)

＜223〉the 216th Xaa is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(217)..(217)

＜223〉the 217th Xaa is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(218)..(218)

＜223〉the 218th Xaa is Gly or Ser;

<220>

<221>misc_feature

<222>(219)..(219)

＜223〉the 219th Xaa is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(222)..(222)

＜223〉the 222nd Xaa is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(223)..(223)

＜223〉the 223rd Xaa is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(224)..(224)

＜223〉the 224th Xaa is Lys or Arg;

<220>

<221>misc_feature

<222>(227)..(227)

＜223〉the 227th Xaa is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(228)..(228)

＜223〉the 228th Xaa is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(230)..(230)

＜223〉the 230th Xaa is Ser, Phe or Leu or removal Leu;

<220>

<221>misc_feature

<222>(231)..(231)

＜223〉the 231st Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(232)..(232)

＜223〉the 232nd Xaa is Thr, Ser or Gly or be removed;

<220>

<221>misc_feature

<222>(237)..(237)

＜223〉the 237th Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(238)..(238)

＜223〉the 238th Xaa is Met or Leu or is removed;

<220>

<221>misc_feature

<222>(241)..(241)

＜223〉the 241st Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(246)..(246)

＜223〉the 246th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(248)..(248)

＜223〉the 248th Xaa is Asn or Lys or is removed;

<400>32

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser Leu Pro

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Phe Xaa Leu

115 120 125

Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val Xaa Pro Trp

130 135 140

Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp Xaa Xaa Asn

145 150 155 160

Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa Xaa Xaa Ala

165 170 175

Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa Xaa Xaa Xaa

180 185 190

Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa Phe

195 200 205

Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg Xaa Xaa Xaa

210 215 220

Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val Ala

225 230 235 240

Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

245

<210>33

<211>330

<212>PRT

＜213〉artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(127)..(127)

＜223〉the 127th Xaa is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

＜223〉the 130th Xaa is Leu, Ala or Met or be removed;

<220>

<221>misc_feature

<222>(134)..(134)

＜223〉the 134th Xaa is Ala or Gly or is removed;

<220>

<221>misc_feature

<222>(137)..(137)

＜223〉the 137th Xaa is Ile, Val or Met or be removed;

<220>

<221>misc_feature

<222>(139)..(139)

＜223〉the 139th Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(140)..(140)

＜223〉the 140th Xaa is Arg or Lys or is removed;

<220>

<221>misc_feature

<222>(141)..(141)

＜223〉the 141st Xaa is Ala or Ser or is removed;

<220>

<221>misc_feature

<222>(142)..(142)

＜223〉the 142nd Xaa is Leu or Ser or is removed;

<220>

<221>misc_feature

<222>(144)..(144)

＜223〉the 144th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(145)..(145)

＜223〉the 145th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(146)..(146)

＜223〉the 146th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(147)..(147)

＜223〉the 147th Xaa is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(149)..(149)

＜223〉the 149th Xaa is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(150)..(150)

＜223〉the 150th Xaa is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(152)..(152)

＜223〉the 152nd Xaa is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(153)..(153)

＜223〉the 153rd Xaa is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

＜223〉the 154th Xaa is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(155)..(155)

＜223〉the 155th Xaa is Tyr or Asn;

<220>

<221>misc_feature

<222>(156)..(156)

＜223〉the 156th Xaa is Ser or Arg;

<220>

<221>misc_feature

<222>(157)..(157)

＜223〉the 157th Xaa is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(158)..(158)

＜223〉the 158th Xaa is Lys or Arg or skips;

<220>

<221>misc_feature

<222>(159)..(159)

＜223〉the 159th Xaa is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(160)..(160)

＜223〉the 160th Xaa is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(161)..(161)

＜223〉the 161st Xaa is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(162)..(162)

＜223〉the 162nd Xaa is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(163)..(163)

＜223〉the 163rd Xaa is His or Leu;

<220>

<221>misc_feature

<222>(164)..(164)

＜223〉the 164th Xaa is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(165)..(165)

＜223〉the 165th Xaa is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(166)..(166)

＜223〉the 166th Xaa is Asp or Ser;

<220>

<221>misc_feature

<222>(167)..(167)

＜223〉the 167th Xaa is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(168)..(168)

＜223〉the 168th Xaa is Arg or skips;

<220>

<221>misc_feature

<222>(169)..(169)

＜223〉the 169th Xaa is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(171)..(171)

＜223〉the 171st Xaa is Ser or Asp;

<220>

<221>misc_feature

<222>(172)..(172)

＜223〉the 172nd Xaa is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(173)..(173)

＜223〉the 173rd Xaa is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(174)..(174)

＜223〉the 174th Xaa is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(175)..(175)

＜223〉the 175th Xaa is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(176)..(176)

＜223〉the 176th Xaa is Leu, Ala, Thr or Val;

<220>

<221>misc_feature

<222>(177)..(177)

＜223〉the 177th Xaa is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(178)..(178)

＜223〉the 178th Xaa is Cys or is removed;

<220>

<221>misc_feature

<222>(179)..(179)

＜223〉the 179th Xaa is Arg or is removed;

<220>

<221>misc_feature

<222>(180)..(180)

＜223〉the 180th Xaa is Leu, Val, Ala or Ser or be removed;

<220>

<221>misc_feature

<222>(181)..(181)

＜223〉the 181st Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(182)..(182)

＜223〉the 182nd Xaa is Phe, Ala, Thr or Met or be removed;

<220>

<221>misc_feature

<222>(183)..(183)

＜223〉the 183rd Xaa is Leu or Val or is removed;

<220>

<221>misc_feature

<222>(184)..(184)

＜223〉the 184th Xaa is Leu, Phe or Met or be removed;

<220>

<221>misc_feature

<222>(188)..(188)

＜223〉the 188th Xaa is Cys, Gly or Ser or be removed;

<220>

<221>misc_feature

<222>(189)..(189)

＜223〉the 189th Xaa is Val, Ile or Met or be removed;

<220>

<221>misc_feature

<222>(190)..(190)

＜223〉the 190th Xaa is Ala, Val, Met or Ile or be removed;

<220>

<221>misc_feature

<222>(194)..(194)

＜223〉the 194th Xaa is Tyr or Cys or is removed;

<220>

<221>misc_feature

<222>(201)..(201)

＜223〉the 201st Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(204)..(204)

<220>

<221>misc_feature

<222>(205)..(205)

<220>

<221>misc_feature

<222>(206)..(206)

<220>

<221>misc_feature

<222>(208)..(208)

＜223〉the 208th Xaa is Arg or Ser or is removed;

<220>

<221>misc_feature

<222>(211)..(211)

＜223〉the 211st Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(212)..(212)

＜223〉the 212nd Xaa is Ser, Gly or Cys or be removed;

<220>

<221>misc_feature

<222>(217)..(217)

＜223〉the 217th Xaa is Val or Ala or is removed;

<220>

<221>misc_feature

<222>(219)..(219)

＜223〉the 219th Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(223)..(223)

＜223〉the 223rd Xaa is Val, Leu or Ile or be removed;

<220>

<221>misc_feature

<222>(226)..(226)

＜223〉the 226th Xaa is Gly, Ala, Met or Val or be removed;

<220>

<221>misc_feature

<222>(227)..(227)

＜223〉the 227th Xaa is Ile, Val, Thr or Ala or be removed;

<220>

<221>misc_feature

<222>(228)..(228)

＜223〉the 228th Xaa is Val or is removed;

<220>

<221>misc_feature

<222>(229)..(229)

＜223〉the 229th Xaa is Lys or is removed;

<220>

<221>misc_feature

<222>(230)..(230)

＜223〉the 230th Xaa is Tyr or Cys;

<220>

<221>misc_feature

<222>(232)..(232)

＜223〉the 232nd Xaa is Tyr or Phe;

<220>

<221>misc_feature

<222>(234)..(234)

＜223〉the 234th Xaa is Asp or Asn;

<220>

<221>misc_feature

<222>(235)..(235)

＜223〉the 235th Xaa is Glu or Val;

<220>

<221>misc_feature

<222>(236)..(236)

＜223〉the 236th Xaa is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(239)..(239)

＜223〉the 239th Xaa is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(240)..(240)

＜223〉the 240th Xaa is Arg or Ser;

<220>

<221>misc_feature

<222>(242)..(242)

＜223〉the 242nd Xaa is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(245)..(245)

＜223〉the 245th Xaa is Asn or Gly or is removed;

<220>

<221>misc_feature

<222>(246)..(246)

＜223〉the 246th Xaa is Tyr or Phe or is removed;

<220>

<221>misc_feature

<222>(248)..(248)

＜223〉the 248th Xaa is Leu or Trp or is removed;

<220>

<221>misc_feature

<222>(250)..(250)

＜223〉the 250th Xaa is Ile or Leu or is removed;

<220>

<221>misc_feature

<222>(252)..(252)

＜223〉the 252nd Xaa is Leu, Phe, Ile or Ser or be removed;

<220>

<221>misc_feature

<222>(254)..(254)

＜223〉the 254th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(255)..(255)

＜223〉the 255th Xaa is Leu or Phe or is removed;

<220>

<221>misc_feature

<222>(256)..(256)

＜223〉the 256th Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(259)..(259)

＜223〉the 259th Xaa is Gly or Leu or is removed;

<220>

<221>misc_feature

<222>(260)..(260)

＜223〉the 260th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(263)..(263)

＜223〉the 263rd Xaa is Leu, Phe or Ile or be removed;

<220>

<221>misc_feature

<222>(268)..(268)

＜223〉the 268th Xaa is Val or Ile or is removed;

<220>

<221>misc_feature

<222>(269)..(269)

＜223〉the 269th Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(270)..(270)

＜223〉the 270th Xaa is Gln, Cys or be removed;

<220>

<221>misc_feature

<222>(271)..(271)

＜223〉the 271st Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(272)..(272)

＜223〉the 272nd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(273)..(273)

＜223〉the 273rd Xaa is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly GlySer or be removed;

<220>

<221>misc_feature

<222>(284)..(284)

＜223〉the 284th Xaa is Thr, Val or Ile or be removed;

<220>

<221>misc_feature

<222>(288)..(288)

＜223〉the 288th Xaa is Ile, Val, Leu or Ala or be removed;

<220>

<221>misc_feature

<222>(293)..(293)

＜223〉the 293rd Xaa is Met, Thr, Ile or Ala or be removed;

<220>

<221>misc_feature

<222>(296)..(296)

＜223〉the 296th Xaa is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(297)..(297)

＜223〉the 297th Xaa is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(298)..(298)

＜223〉the 298th Xaa is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(299)..(299)

＜223〉the 299th Xaa is Gly or Ser;

<220>

<221>misc_feature

<222>(300)..(300)

＜223〉the 300th Xaa is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(303)..(303)

＜223〉the 303rd Xaa is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(304)..(304)

＜223〉the 304th Xaa is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(305)..(305)

＜223〉the 305th Xaa is Lys or Arg;

<220>

<221>misc_feature

<222>(308)..(308)

＜223〉the 308th Xaa is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(309)..(309)

＜223〉the 309th Xaa is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(311)..(311)

＜223〉the 311st Xaa is Ser, Phe or Leu or removal Leu;

<220>

<221>misc_feature

<222>(312)..(312)

＜223〉the 312nd Xaa is Phe or Leu or is removed;

<220>

<221>misc_feature

<222>(313)..(313)

＜223〉the 313rd Xaa is Thr, Ser or Gly or be removed;

<220>

<221>misc_feature

<222>(318)..(318)

＜223〉the 318th Xaa is Leu or Met or is removed;

<220>

<221>misc_feature

<222>(319)..(319)

＜223〉the 319th Xaa is Met or Leu or is removed;

<220>

<221>misc_feature

<222>(322)..(322)

＜223〉the 322nd Xaa is Ile or Val or is removed;

<220>

<221>misc_feature

<222>(327)..(327)

＜223〉the 327th Xaa is Val or Leu or is removed;

<220>

<221>misc_feature

<222>(329)..(329)

＜223〉the 329th Xaa is Asn or Lys or is removed;

<400>33

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser Leu Pro

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Asn Xaa Ile

115 120 125

His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa Xaa Ser Xaa

130 135 140

Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

145 150 155 160

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

165 170 175

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa Xaa Ala Asn

180 185 190

Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa Xaa Phe Xaa

195 200 205

Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val Xaa Pro

210 215 220

Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp Xaa Xaa

225 230 235 240

Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa Xaa Xaa

245 250 255

Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa Xaa Xaa

260 265 270

Xaa Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa

275 280 285

Phe Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg Xaa Xaa

290 295 300

Xaa Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val

305 310 315 320

Ala Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

325 330

<210>34

<211>227

<212>PRT

＜213〉people

<400>34

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

1 5 10 15

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Lys

225

<210>35

<211>381

<212>PRT

＜213〉artificial sequence

<400>35

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr

35 40 45

Gly Asp Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu

50 55 60

Leu Val Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr

65 70 75 80

Pro Ala Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp

85 90 95

His His Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp

100 105 110

Gly Gln Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser

115 120 125

Gln Cys Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala

130 135 140

Lys Met Tyr Ser Ser Phe Gln Gly Pro Gly Asp Lys Thr His Thr Cys

145 150 155 160

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

165 170 175

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

180 185 190

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

195 200 205

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

210 215 220

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

225 230 235 240

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

245 250 255

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

260 265 270

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

275 280 285

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

290 295 300

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

305 310 315 320

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

325 330 335

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

340 345 350

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

355 360 365

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

370 375 380

<210>36

<211>340

<212>PRT

＜213〉artificial sequence

<400>36

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val Leu Lys

35 40 45

Ala Ser Ser Val Leu Val Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser

50 55 60

Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly

65 70 75 80

Ala Val Ala Gly Cys Arg Val Ala Ala Val Phe Met Gln Tyr Gly Ile

85 90 95

Val Ala Asn Tyr Cys Trp Leu Leu Val Glu Gly Leu Tyr Leu Gly Pro

100 105 110

Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu

115 120 125

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

130 135 140

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

145 150 155 160

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

165 170 175

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

180 185 190

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

195 200 205

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

210 215 220

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

225 230 235 240

Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val

245 250 255

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

260 265 270

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

275 280 285

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

290 295 300

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

305 310 315 320

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

325 330 335

Ser Pro Gly Lys

340

<210>37

<211>318

<212>PRT

＜213〉artificial sequence

<400>37

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Thr Leu Thr Leu Ile Pro Leu Leu Gly Val His Glu Val Val

35 40 45

Phe Ala Phe Val Thr Asp Glu His Ala Gln Gly Thr Leu Arg Ser Ala

50 55 60

Lys Leu Phe Phe Asp Leu Phe Leu Ser Ser Phe Gln Gly Leu Leu Val

65 70 75 80

Ala Val Leu Tyr Cys Phe Leu Asn Gly Pro Gly Asp Lys Thr His Thr

85 90 95

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

100 105 110

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

115 120 125

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

130 135 140

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

145 150 155 160

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

165 170 175

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

180 185 190

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

195 200 205

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

210 215 220

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

225 230 235 240

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

245 250 255

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

260 265 270

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

275 280 285

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

290 295 300

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

305 310 315

<210>38

<211>316

<212>PRT

＜213〉artificial sequence

<400>38

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Val Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser Gln Lys Ile

35 40 45

Gly Asp Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly Ala Val Ala

50 55 60

Gly Gly Gly Gly Ser Asp Glu His Ala Gln Gly Thr Leu Arg Ser Ala

65 70 75 80

Lys Leu Phe Phe Asp Leu Gly Pro Gly Asp Lys Thr His Thr Cys Pro

85 90 95

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe

100 105 110

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

115 120 125

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

130 135 140

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

145 150 155 160

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

165 170 175

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

180 185 190

Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala

195 200 205

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg

210 215 220

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

225 230 235 240

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

245 250 255

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

260 265 270

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

275 280 285

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

290 295 300

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

305 310 315

<210>39

<211>261

<212>PRT

＜213〉artificial sequence

<400>39

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

35 40 45

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

50 55 60

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

65 70 75 80

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

85 90 95

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

100 105 110

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

115 120 125

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

130 135 140

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

145 150 155 160

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

165 170 175

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

180 185 190

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

195 200 205

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

210 215 220

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

225 230 235 240

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

245 250 255

Leu Ser Pro Gly Lys

260

<210>40

<211>704

<212>PRT

＜213〉artificial sequence

<400>40

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln

35 40 45

Lys Trp Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp

50 55 60

Pro Pro Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr

65 70 75 80

Ala Cys Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys

85 90 95

Pro Trp Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr

100 105 110

Arg Phe Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser

115 120 125

Leu Pro Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu

130 135 140

Arg Ser Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Ile Ile Tyr Thr

145 150 155 160

Val Gly Tyr Ala Leu Ser Phe Ser Ala Leu Val Ile Ala Ser Ala Ile

165 170 175

Leu Leu Gly Phe Arg His Leu His Cys Thr Arg Asn Tyr Ile His Leu

180 185 190

Asn Leu Phe Ala Ser Phe Ile Leu Arg Ala Leu Ser Val Phe Ile Lys

195 200 205

Asp Ala Ala Leu Lys Trp Met Tyr Ser Thr Ala Ala Gln Gln His Gln

210 215 220

Trp Asp Gly Leu Leu Ser Tyr Gln Asp Ser Leu Ser Cys Arg Leu Val

225 230 235 240

Phe Leu Leu Met Gln Tyr Cys Val Ala Ala Asn Tyr Tyr Trp Leu Leu

245 250 255

Val Glu Gly Val Tyr Leu Tyr Thr Leu Leu Ala Phe Ser Val Phe Ser

260 265 270

Glu Gln Trp Ile Phe Arg Leu Tyr Val Ser Ile Gly Trp Gly Val Pro

275 280 285

Leu Leu Phe Val Val Pro Trp Gly Ile Val Lys Tyr Leu Tyr Glu Asp

290 295 300

Glu Gly Cys Trp Thr Arg Asn Ser Asn Met Asn Tyr Trp Leu Ile Ile

305 310 315 320

Arg Leu Pro Ile Leu Phe Ala Ile Gly Val Asn Phe Leu Ile Phe Val

325 330 335

Arg Val Ile Cys Ile Val Val Ser Lys Leu Lys Ala Asn Leu Met Cys

340 345 350

Lys Thr Asp Ile Lys Cys Arg Leu Ala Lys Ser Thr Leu Thr Leu Ile

355 360 365

Pro Leu Leu Gly Thr His Glu Val Ile Phe Ala Phe Val Met Asp Glu

370 375 380

His Ala Arg Gly Thr Leu Arg Phe Ile Lys Leu Phe Thr Glu Leu Ser

385 390 395 400

Phe Thr Ser Phe Gln Gly Leu Met Val Ala Ile Leu Tyr Cys Phe Val

405 410 415

Asn Asn Glu Val Gln Leu Glu Phe Arg Lys Ser Trp Glu Arg Trp Arg

420 425 430

Leu Glu His Leu His Ile Gln Arg Asp Ser Ser Met Lys Pro Leu Lys

435 440 445

Cys Pro Thr Ser Ser Leu Ser Ser Gly Ala Thr Ala Gly Ser Ser Met

450 455 460

Tyr Thr Ala Thr Cys Gln Ala Ser Cys Ser Gly Pro Gly Asp Lys Thr

465 470 475 480

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

485 490 495

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

500 505 510

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

515 520 525

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

530 535 540

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

545 550 555 560

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

565 570 575

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

580 585 590

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

595 600 605

Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys

610 615 620

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

625 630 635 640

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

645 650 655

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

660 665 670

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

675 680 685

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

690 695 700

<210>41

<211>386

<212>PRT

＜213〉artificial sequence

<400>4l

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln

35 40 45

Lys Trp Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp

50 55 60

Pro Pro Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr

65 70 75 80

Ala Cys Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys

85 90 95

Pro Trp Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr

100 105 110

Arg Phe Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser

115 120 125

Leu Pro Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu

130 135 140

Arg Ser Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Gly Pro Gly Asp

145 150 155 160

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

165 170 175

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

180 185 190

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

195 200 205

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

210 215 220

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

225 230 235 240

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

245 250 255

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

260 265 270

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

275 280 285

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu

290 295 300

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

305 310 315 320

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

325 330 335

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

340 345 350

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

355 360 365

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

370 375 380

Gly Lys

385

<210>42

<211>339

<212>PRT

＜213〉artificial sequence

<400>42

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Asn Tyr Ile His Leu Asn Leu Phe Ala Ser Phe Ile Leu Arg

35 40 45

Ala Leu Ser Val Phe Ile Lys Asp Ala Ala Leu Lys Trp Met Tyr Ser

50 55 60

Thr Ala Ala Gln Gln His Gln Trp Asp Gly Leu Leu Ser Tyr Gln Asp

65 70 75 80

Ser Leu Ser Cys Arg Leu Val Phe Leu Leu Met Gln Tyr Cys Val Ala

85 90 95

Ala Asn Tyr Tyr Trp Leu Leu Val Glu Gly Val Tyr Leu Gly Pro Gly

100 105 110

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

115 120 125

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

130 135 140

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

145 150 155 160

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

165 170 175

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

180 185 190

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

195 200 205

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

210 215 220

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

225 230 235 240

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

245 250 255

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

260 265 270

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

275 280 285

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

290 295 300

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

305 310 315 320

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

325 330 335

Pro Gly Lys

<210>43

<211>328

<212>PRT

＜213〉artificial sequence

<400>43

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Phe Arg Leu Tyr Val Ser Ile Gly Trp Gly Val Pro Leu Leu

35 40 45

Phe Val Val Pro Trp Gly Ile Val Lys Tyr Leu Tyr Glu Asp Glu Gly

50 55 60

Cys Trp Thr Arg Asn Ser Asn Met Asn Tyr Trp Leu Ile Ile Arg Leu

65 70 75 80

Pro Ile Leu Phe Gly Ile Gly Val Asn Phe Leu Ile Phe Val Arg Val

85 90 95

Ile Cys Gly Pro Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

100 105 110

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

115 120 125

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

130 135 140

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

145 150 155 160

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

165 170 175

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

180 185 190

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

195 200 205

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

210 215 220

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

225 230 235 240

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

245 250 255

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

260 265 270

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

275 280 285

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

290 295 300

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

305 310 315 320

Ser Leu Ser Leu Ser Pro Gly Lys

325

<210>44

<211>321

<212>PRT

＜213〉artificial sequence

<400>44

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Thr His Glu Val

35 40 45

Ile Phe Ala Phe Val Met Asp Glu His Ala Arg Gly Thr Leu Arg Phe

50 55 60

Ile Lys Leu Phe Thr Glu Leu Ser Phe Thr Ser Phe Gln Gly Leu Met

65 70 75 80

Val Ala Ile Leu Tyr Cys Phe Val Asn Asn Glu Gly Pro Gly Asp Lys

85 90 95

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

100 105 110

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

115 120 125

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

130 135 140

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

145 150 155 160

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

165 170 175

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

180 185 190

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

195 200 205

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

210 215 220

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

225 230 235 240

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

245 250 255

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

260 265 270

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

275 280 285

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

290 295 300

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

305 310 315 320

Lys

<210>45

<211>399

<212>PRT

＜213〉artificial sequence

<400>45

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Asn Tyr Ile His Leu Asn Leu Phe Ala Ser Phe Ile Leu Arg

35 40 45

Ala Leu Ser Val Phe Ile Lys Asp Ala Ala Leu Lys Trp Met Tyr Ser

50 55 60

Thr Ala Ala Gln Gln His Gln Trp Asp Gly Leu Leu Ser Tyr Gln Asp

65 70 75 80

Ser Leu Ser Cys Arg Leu Val Phe Leu Leu Met Gln Tyr Cys Val Ala

85 90 95

Ala Asn Tyr Tyr Trp Leu Leu Val Glu Gly Val Tyr Leu Gly Pro Gly

100 105 110

Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Thr His Glu Val Ile Phe

115 120 125

Ala Phe Val Met Asp Glu His Ala Arg Gly Thr Leu Arg Phe Ile Lys

130 135 140

Leu Phe Thr Glu Leu Ser Phe Thr Ser Phe Gln Gly Leu Met Val Ala

145 150 155 160

Ile Leu Tyr Cys Phe Val Asn Asn Glu Gly Pro Gly Asp Lys Thr His

165 170 175

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

180 185 190

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

195 200 205

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

210 215 220

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

225 230 235 240

Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser

245 250 255

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

260 265 270

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile

275 280 285

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

290 295 300

Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

305 310 315 320

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

325 330 335

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

340 345 350

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

355 360 365

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

370 375 380

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

385 390 395

Claims

1. the fusion rotein of a hyperglycemic-glycogenolytic factor similar peptide-1 (GLP-1) is characterized in that being made up of polypeptide A-polypeptide B; Wherein,

Polypeptide A is GLP-1 (7-37) [serial ID: NO:1], and its sequence is:

His-Xaa2-Xaa3-Gly-Xaa5-Xaa6-Thr-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Xaa25-Xaa26-Leu-Xaa28-Xaa29-Xaa30-Xaa31

Xaa2 is in the formula: Ala, Gly, Ser, Thr; Xaa3 is: Glu, Asp, Gln, Asn; Xaa5 is: Thr, Arg, Ile; Xaa6 is: Phe, Tyr, Leu; Xaa8 is: Ser, Asn; Xaa9 is: Asp, Asn; Xaa10 is: Val, Ile, Met, Ala; Xaa11 is: Ser, Thr, Ala, Asp; Xaa12 is: Ser, Gln, Glu, Asn, Thr; Xaa13 is: Tyr, Phe, Gln, His, Leu; Xaa14 is: Leu, Thr, Ser; Xaa15 is: Glu, Gln, Asn, Asp, Arg, Lys; Xaa16 is: Gly, Glu, Asp, Gln, Asn, Arg, Lys; Xaa17 is: Gln, Lys, Leu, Phe; Xaa18 is: Ala, Lys; Xaa19 is: Ala, Thr, Ile, Ser; Xaa20 is: Lys, Arg, Gln; Xaa21 is: Glu, Asp, Asn, Ala, Ser, Lys, Arg; Xaa23 is: Ile, Val; Xaa24 is: Ala, Ser, Asp, Glu, Gly, Thr; Xaa25 is: Trp, Arg, Lys, Ser; Xaa27 is: Val, Lys, Ile, Ser, Ala; Xaa28 is: Lys, Arg, Asn, Gln, Ser, Ala, Thr; Xaa29 is: Gly, Tyr, Ser; Xaa30 is: Arg, Lys, Gln, Asp, Asn, Gly, Ala, Pro; Xaa31 is: Gly, Pro, Val, Arg, Lys, Ala or be removed;

Polypeptide B is the acceptor of any polypeptide in human glucagon receptor or the hyperglycemic-glycogenolytic factor family.

2. according to the fusion rotein of claim 1, it is characterized in that: also have joint in the middle of polypeptide A and the polypeptide B, be selected from:

(Gly-Thr-Gly) n, (Gly-Ala-Pro) n, (Gly-Pro-Gly) n or (Gly-Gly-Gly-Gly-Ser) n;

Wherein n is 1,2,3,4,5,6.

3, fusion rotein according to claim 1 is characterized in that glucagon receptor can be any in the following sequence:

(1) whole glucagon receptor sequence [serial ID NO:2], its sequence is:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQVMYTVGYSLSLGALLLALAILGGLSKLHCTRNAIHANLFASFVLKASSVLVIDGLLRTRYSQKIGDDLSVSTWLSDGAVAGCRVAAVFMQYGIVANYCWLLVEGLYLHNLLGLATLPERSFFSLYLGIGWGAPMLFVVPWAVVKCLFENVQCWTSNDNMGFWWILRFPVFLAILINFFIFVRIVQLLVAKLRARQMHHTDYKFRLAKSTLTLIPLLGVHEVVFAFVTDEHAQGTLRSAKLFFDLFLSSFQGLLVAVLYCFLNKEVQSELRRRWHRWRLGKVLWEERNTSNHRASSSPGHGPPSKELQFGRGGGSQDSSAETPLAGGLPRLAESPF

(2) glucagon receptor N-terminal membrane ectodomain [serial ID NO:3], its sequence is:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQ

(3) glucagon receptor functional zone-1 mainly add that by the glucagon receptor first film outer ring film district of striding at its two ends forms [serial ID NO:4], and its sequence is:

Xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa2

Xaa1 contains following sequence: NAIHANLFASFVLKASSVLV in the formula

From Xaa1 N-end, all amino acid can be removed one by one;

Xaa2 contains following sequence: CRVAAVFMQYGIVANYCWLLVEGLYL in the formula

From Xaa2 C-end, all amino acid can be removed one by one;

(4) glucagon receptor functional zone-2 mainly add that by glucagon receptor the 2nd film outer ring the film district of striding at its two ends forms [serial ID NO:5], and its sequence is:

Xaa3-KCLFENVQCWTSNDNMGF-Xaa4

Xaa3 contains following sequence: FSLYLGIGWGAPMLFVVPWAVV in the formula

From Xaa3 N-end, all amino acid can be removed one by one;

Xaa4 contains following sequence: WWILRFPVFLAILINFFIFVRIV in the formula

From Xaa4 C-end, all amino acid can be removed one by one;

(5) glucagon receptor functional zone-3 mainly add that by glucagon receptor the 3rd film outer ring the film district of striding at its two ends forms [serial ID NO:6], and its sequence is:

Xaa5-DEHAQGTLRSAKLFFD-Xaa6

Xaa5 contains from following sequence: TLTLIPLLGVHEVVFAFVT in the formula

From Xaa5 N-end, all amino acid can be removed one by one;

Xaa6 contains following sequence: LFLSSFQGLLVAVLYCFLN in the formula

From Xaa5 C-end, all amino acid can be removed one by one;

(6) described (3)-intermediate head-described (4) have following sequential structure [serial ID NO:7]:

Xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa2-intermediate head-Xaa3-KCLFENVQCWTSNDNMGF-Xaa4

(7) described (3)-intermediate head-described (5) have following sequential structure [serial ID NO:8]:

Xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa2-intermediate head-Xaa5-DEHAQGTLRSAKLFFD-Xaa6

(8) described (4)-intermediate head described-(5), have following sequential structure [serial ID NO:9]: Xaa3-KCLFENVQCWTSNDNMGF-Xaa4-intermediate head-Xaa5-DEHAQGTLRSAKLFFD-Xaa6

(9) described (3)-intermediate head-described (4)-intermediate head-described (5) have following sequential structure [serial ID NO:10]:

Xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa2-intermediate head-Xaa3-KCLFENVQCWTSNDNMGF-Xaa4-intermediate head-Xaa5-DEHAQGTLRSAKLFFD-Xaa6

(10) described (2)-intermediate head-(3) have following sequential structure [serial ID NO:11]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISC PWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKM YSSFQ-intermediate head-Xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa2

(11) described (2)-intermediate head-(4) have following sequential structure [serial ID NO:12]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISC PWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKM YSSFQ-intermediate head-Xaa3-KCLFENVQCWTSNDNMGF-Xaa4

(12) described (2)-intermediate head-(5) have following sequential structure [serial ID NO:13]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISC PWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKM YSSFQ-intermediate head-Xaa5-DEHAQGTLRSAKLFFD-Xaa6

(13) described (2)-intermediate head-(6) have following sequential structure [serial ID NO:14]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISC PWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKM YSSFQ-intermediate head-Xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa2-intermediate head-Xaa3-KCLFENVQCWTSNDNMGF-Xaa4

(14) described (2)-intermediate head-(7) have following sequential structure [serial ID NO:15]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISC PWYLPWHHKQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMY SSFQ-intermediate head-Xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa2-intermediate head-Xaa5-DEHAQGTLRSAKLFFD-Xaa6

(15) described (2)-intermediate head-(8) have following sequential structure [serial ID NO:16]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISC PWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKM YSSFQ-intermediate head-Xaa3-KCLFENVQCWTSNDNMGF-Xaa4-intermediate head-Xaa5-DEHAQGTLRSAKLFFD-Xaa6

(16) described (2)-intermediate head-(9) have following sequential structure [serial ID NO:17]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISC PWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKM YSSFQ-intermediate head-Xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa2-intermediate head-Xaa3-KCLFENVQCWTSNDNMGF-Xaa4-intermediate head-Xaa5-DEHAQGTLRSAKLFFD-Xaa6.

4, according to the described fusion rotein of claim 1, its polypeptide B can be selected from GLP-1 acceptor, the GLP-2 acceptor in the glucagon receptor family, following any one polypeptide in the glucose dependency Regular Insulin nutrient substance polypeptide receptor:

(1) whole GLP-1 receptor sequence, its sequence are [serial ID NO:18]:

RPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLFCNRTFDEYACWPDGEPGSFVNVSCPWYLPWASSVPQGHVYRFCTAEGLWLQKDNSSLPWRDLSECEESKRGERSSPEEQLLFLYIIYTVGYALSFSALVIASAILLGFRHLHCTRNYIHLNLFASFILRALSVFIKDAALKWMYSTAAQQHQWDGLLSYQDSLSCRLVFLLMQYCVAANYYWLLVEGVYLYTLLAFSVFSEQWIFRLYVSIGWGVPLLFVVPWGIVKYLYEDEGCWTRNSNMNYWLIIRLPILFAIGVNFLIFVRVICIVVSKLKANLMCKTDIKCRLA KSTLTLIPLLGTHEVIFAFVMDEHARGTLRFIKLFTELSFTSFQGLMVAILYCFVNNEVQLEFRKSWERWRLEHLHIQRDSSMKPLKCPTSSLSSGATAGSSMYTATCQASCS

(2) GLP-1 acceptor N-terminal membrane ectodomain; Its sequence is [serial ID NO:19]:

RPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLFCNRTFDEYACWPDGEPGSFVNVSCPWYLPWASSVPQGHVYRFCTAEGLWLQKDNSSLPWRDLSECEESKRGERSSPEEQLLFLY

(3) functional zone-1 of any polypeptide receptor in the hyperglycemic-glycogenolytic factor family, mainly the first film outer ring by acceptor adds that the film district of striding at its two ends forms, its sequence is [serial ID NO:20]:

Asn-Xaa2-Ile-His-Xaa5-Asn-Leu-Phe-Xaa9-Ser-Phe-Xaa12-Leu-Xaa14-Xaa13-Xaa15-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Xaa21-Asp-Xaa23-Xaa24-Leu-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43-Leu-Xaa45-Xaa46-Xaa47-Xaa48-Xaa49-Xaa50-Xaa51-Xaa52-Xaa53-Xaa54-Xaa55-Xaa56-Xaa57-Xaa58-Met-Gln-Tyr-Xaa62-Xaa63-Xaa64-Ala-Asn-Tyr-Xaa68-Trp-Leu-Leu-Val-Glu-Gly-Xaa75-Tyr-Leu

Wherein Xaa2 is Tyr, Ala or be removed; Xaa5 is Leu, Ala, Met or be removed; Xaa9 is Ala, Gly or be removed; Xaa12 is Ile, Val, Met or be removed; Xaa13 is Leu, Val or be removed; Xaa14 is Arg, Lys or be removed; Xaa15 is Ala, Ser or be removed; Xaa16 is Leu, Ser or be removed; Xaa18 is Val, Leu or be removed; Xaa19 is Phe, Leu or be removed; Xaa20 is Ile, Val or be removed; Xaa21 is Lys, Arg, Gln, Asp, Glu, Asn, Ile; Xaa23 is Ala, Gly, Thr, Trp, Val, Arg, Ile; Xaa24 is Ala, Leu, Val; Xaa26 is Lys, Arg, Asp; Xaa27 is Trp, Thr, Gln, Asn; Xaa28 is Met, Arg, Ser; Xaa29 is Tyr, Asn; Xaa30 is Ser, Arg; Xaa31 is Thr, Gln, Ala; Xaa32 is Lys, Arg or skip; Xaa33 is Ala, Ile, Ser; Xaa34 is Ala, Gly, Ile; Xaa35 is Gln, Asp, Pro, Glu, Ile; Xaa36 is Gln, Asp, Glu, Ser, Asn; Xaa37 is His, Leu; Xaa38 is Gln, Ser, Tyr, Glu; Xaa39 is Trp, Val, Gln; Xaa40 is Asp, Ser; Xaa41 is Gly, Thr, Val, Ser, Ala; Xaa42 is R or skips; Xaa43 is Leu, Trp, Arg, Thr, Tyr; Xaa45 is Ser, Asp; Xaa46 is Tyr, Asp, Thr; Xaa47 is Gln, Glu, Gly; Xaa48 is Asp, Ala, Thr; Xaa49 is Ser, Val, Leu, Met; Xaa50 is Leu, Ala, Thr, Val; Xaa51 is Ser, Gly, Ala; Xaa52 is Cys or is removed; Xaa53 is Arg or is removed; Xaa54 is Leu, Val, Ala, Ser or be removed; Xaa55 is Val, Ala or be removed; Xaa56 is Phe, Ala, Thr, Met or be removed; Xaa57 is Leu, Val or be removed; Xaa58 is Leu, Phe, Met or be removed; Xaa62 is Cys, Gly, Ser or be removed; Xaa63 is Val, Ile, Met or be removed; Xaa64 is Ala, Val, Met, Ile or be removed; Xaa68 is Tyr, Cys or be removed; Xaa75 is Val, Leu or be removed; Xaa78 is Tyr, His or be removed; Before Xaa20, from the N-end, all amino acid can be removed one by one; As be removed, then all amino acid in its front also are removed; After Xaa52, from the C-end, all amino acid can be removed one by one; As be removed, then all amino acid in its back also are removed;

(4) functional zone-2 of any polypeptide receptor in the hyperglycemic-glycogenolytic factor family, mainly the 2nd film outer ring by acceptor adds that the film district of striding at its two ends forms, its sequence is [serial ID NO:21]:

Phe-Xaa2-Leu-Tyr-Xaa5-Xaa6-Ile-Gly-Trp-Gly-Xaa11-Pro-Xaa13--Leu-Phe-Val-Xaa17-Pro-Trp-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Leu-Xaa26-Glu-Xaa28-Xaa29-Xaa30-Cys-Trp-Xaa33-Xaa34-Asn-Xaa36-Asn-Met-Xaa39-Xaa40-Trp-Xaa42-Ile-Xaa44-Arg-Xaa46-Pro-Xaa48-Xaa49-Xaa50-Ala-Ile-Xaa53-Xaa54-Asn-Phe-Xaa57-Ile-Phe-Val-Arg-Xaa62-Xaa63-Xaa64

Wherein Xaa2 is Arg, Ser or be removed; Xaa5 is Val, Leu or be removed; Xaa6 is Ser, Gly, Cys or be removed; Xaa11 is Val, Ala or be removed; Xaa13 is Leu, Met or be removed; Xaa17 is Val, Leu, Ile or be removed; Xaa20 is Gly, Ala, Met, Val or be removed; Xaa21 is Ile, Val, Thr, Ala or be removed; Xaa22 is Val or is removed; Xaa23 is Lys or is removed; Xaa24 is Tyr, Cys; Xaa26 is Tyr, Phe; Xaa28 is Asp, Asn; Xaa29 is Glu, Val; Xaa30 is Gly, Gln, Glu, Asp; Xaa33 is Thr, Glu, Ser; Xaa34 is Arg, Ser; Xaa36 is Ser, Asp, Asn, Met; Xaa39 is Asn, Gly or be removed; Xaa40 is Tyr, Phe or be removed; Xaa42 is Leu, Trp or be removed; Xaa44 is Ile, Leu or be removed; Xaa46 is Leu, Phe, Ile, Ser or be removed; Xaa48 is Ile, Val or be removed; Xaa49 is Leu, Phe or be removed; Xaa50 is Phe, Leu or be removed; Xaa53 is Gly, Leu or be removed; Xaa54 is Val, Ile or be removed; Xaa57 is Leu, Phe, Ile or be removed; Xaa62 is Val, Ile or be removed; Xaa63 is Ile, Val or be removed; Xaa64 is Gln, Cys or be removed; Before Xaa23, from the N-end, all amino acid can be removed one by one; As be removed, then all amino acid in its front also are removed; After Xaa39, from the C-end, all amino acid can be removed one by one; As be removed, then all amino acid in its back also are removed;

(5) functional zone-3 of any polypeptide receptor in the hyperglycemic-glycogenolytic factor family, mainly the 3rd film outer ring by acceptor adds that the film district of striding at its two ends forms, its sequence is [serial ID NO:22]:

Ser-Thr-Leu-Thr-Leu-Ile-Pro-Leu-Leu-Gly-Xaa11-His-Glu-Val-Xaa15-Phe-Ala-Phe-Val-Xaa20-Asp-Glu-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Leu-Arg-Xaa30-Xaa31-Xaa32-Leu-Phe-Xaa35-Xaa36-Leu-Xaa38-Xaa39-Xaa40-Ser-Phe-Gln-Gly-Xaa45-Xaa46-Val-Ala-Xaa49-Leu-Tyr-Cys-Phe-Xaa54-Asn-Xaa56-Glu

Wherein Xaa11 is Thr, Val, Ile or be removed; Xaa15 is Ile, Val, Leu, Ala or be removed; Xaa20 is Met, Thr, Ile, Ala or be removed; Xaa23 is His, Pro, Gln, Thr; Xaa24 is Ala, Lys, Val, Thr; Xaa25 is Arg, Lys, Gln, Glu; Xaa26 is Gly, Ser; Xaa27 is Thr, Leu, Phe, Ala; Xaa30 is Phe, Ser, Leu; Xaa31 is Ile, Ala, Val, Thr; Xaa32 is Lys, Arg; Xaa35 is Thr, Phe, Tyr, Ile; Xaa36 is Glu, Asp, Gln, Asn; Xaa38 is Ser, Phe, Leu or removal Leu; Xaa39 is Phe, Leu or be removed; Xaa40 is Thr, Ser, Gly or be removed; Xaa45 is Leu, Met or be removed; Xaa46 is Met, Leu or be removed; Xaa49 is Ile, Val or be removed; Xaa54 is Val, Leu or be removed; Xaa56 is Asn, Lys or be removed; Before Xaa20, from the N-end, all amino acid can be removed one by one; As be removed, then all amino acid in its front also are removed; After Xaa38, from the C-end, all amino acid can be removed one by one; As be removed, then all amino acid in its back also are removed;

(6) described (3)-intermediate head-described (4) have following array structure [serial ID NO:23]:

Asn-Xaa2-Ile-His-Xaa5-Asn-Leu-Phe-Xaa9-Ser-Phe-Xaa12-Leu-Xaa14-Xaa13-Xaa15-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Xaa21-Asp-Xaa23-Xaa24-Leu-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43-Leu-Xaa45-Xaa46-Xaa47-Xaa48-Xaa49-Xaa50-Xaa51-Xaa52-Xaa53-Xaa54-Xaa55-Xaa56-Xaa57-Xaa58-Met-Gln-Tyr-Xaa62-Xaa63-Xaa64-Ala-Asn-Tyr-Xaa68-Trp-Leu-Leu-Val-Glu-Gly-Xaa75-Tyr-Leu--Phe-Xaa2-Leu-Tyr-Xaa5-Xaa6-Ile-Gly-Trp-Gly-Xaa11-Pro-Xaa13-Leu-Phe-Val-Xaa17-Pro-Trp-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Leu-Xaa26-Glu-Xaa28-Xaa29-Xaa30-Cys-Trp-Xaa33-Xaa34-Asn-Xaa36-Asn-Met-Xaa39-Xaa40-Trp-Xaa42-Ile-Xaa44-Arg-Xaa46-Pro-Xaa48-Xaa49-Xaa50-Ala-Ile-Xaa53-Xaa54-Asn-Phe-Xaa57-Ile-Phe-Val-Arg-Xaa62-Xaa63-Xaa64

(7) described (3)-intermediate head-described (5) have following array structure [serial ID NO:24]:

Asn-Xaa2-Ile-His-Xaa5-Asn-Leu-Phe-Xaa9-Ser-Phe-Xaa12-Leu-Xaa14-Xaa13-Xaa15-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Xaa21-Asp-Xaa23-Xaa24-Leu-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43-Leu-Xaa45-Xaa46-Xaa47-Xaa48-Xaa49-Xaa50-Xaa51-Xaa52-Xaa53-Xaa54-Xaa55-Xaa56-Xaa57-Xaa58-Met-Gln-Tyr-Xaa62-Xaa63-Xaa64-Ala-Asn-Tyr-Xaa68-Trp-Leu-Leu-Val-Glu-Gly-Xaa75-Tyr-Leu--Ser-Thr-Leu-Thr-Leu-Ile-Pro-Leu-Leu-Gly-Xaa11-His-Glu-Val-Xaa15-Phe-Ala-Phe-Val-Xaa20-Asp-Glu-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Leu-Arg-Xaa30-Xaa31-Xaa32-Leu-Phe-Xaa35-Xaa36-Leu-Xaa38-Xaa39-Xaa40-Ser-Phe-Gln-Gly-Xaa45-Xaa46-Val-Ala-Xaa49-Leu-Tyr-Cys-Phe-Xaa54-Asn-Xaa56-Glu

(8) described (4)-intermediate head-described (5) have following array structure [serial ID NO:25]:

Phe-Xaa2-Leu-Tyr-Xaa5-Xaa6-Ile-Gly-Trp-Gly-Xaa11-Pro-Xaa 13--Leu-Phe-Val-Xaa17-Pro-Trp-Xaa20-Xaa21-Xaa22-Xaa23-Xa a24-Leu-Xaa26-Glu-Xaa28-Xaa29-Xaa30-Cys-Trp-Xaa33-Xaa34-Asn-Xaa36-Asn-Met-Xaa39-Xaa40-Trp-Xaa42-Ile-Xaa44-Arg-Xa a46-Pro-Xaa48-Xaa49-Xaa50-Ala-Ile-Xaa53-Xaa54-Asn-Phe-Xa a57-Ile-Phe-Val-Rro-Xaa62-Xaa63-Xaa64-transition joint-Ser-Thr-Leu-Thr-Leu-Ile-Pro-Leu-Leu-Gly-Xaa11-His-Glu-Va l-Xaa15-Phe-Ala-Phe-Val-Xaa20-Asp-Glu-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Leu-Arg-Xaa30-Xaa31-Xaa32-Leu-Phe-Xaa35-Xaa3 6-Leu-Xaa38-Xaa39-Xaa40-Ser-Phe-Gln-Gly-Xaa45-Xaa46-Val-Ala-Xaa49-Leu-Tyr-Cys-Phe-Xaa54-Asn-Xaa56-6lu

(9) described (3)-intermediate head-described (4)-intermediate head-described (5) have following array structure [serial ID NO:26]:

Asn-Xaa2-Ile-His-Xaa5-Asn-Leu-Phe-Xaa9-Ser-Phe-Xaa12-Leu-Xaa14-Xaa13-Xaa15-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Xaa21-Asp-Xaa23-Xaa24-Leu-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43-Leu-Xaa45-Xaa46-Xaa47-Xaa48-Xaa49-Xaa50-Xaa51-Xaa52-Xaa53-Xaa54-Xaa55-Xaa56-Xaa57-Xaa58-Met-Gln-Tyr-Xaa62-Xaa63-Xaa64-Ala-Asn-Tyr-Xaa68-Trp-Leu-Leu-Val-Glu-Gly-Xaa75-Tyr-Leu--Phe-Xaa2-Leu-Tyr-Xaa5-Xaa6-Ile-Gly-Trp-Gly-Xaa11-Pro-Xaa13-Leu-Phe-Val-Xaa17-Pro-Trp-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Leu-Xaa26-Glu-Xaa28-Xaa29-Xaa30-Cys-Trp-Xaa33-Xaa34-Asn-Xaa36-Asn-Met-Xaa39-Xaa40-Trp-Xaa42-Ile-Xaa44-Arg-Xaa46-Pro-Xaa48-Xaa49-Xaa50-Ala-Ile-Xaa53-Xaa54-Asn-Phe-Xaa57-Ile-Phe-Val-Arg-Xaa62-Xaa63-Xaa64--Ser-Thr-Leu-Thr-Leu-Ile-Pro-Leu-Leu-Gly-Xaa11-His-Glu-Val-Xaa15-Phe-Ala-Phe-Val-Xaa20-Asp-Glu-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Leu-Arg-Xaa30-Xaa31-Xaa32-Leu-Phe-Xaa35-Xaa36-Leu-Xaa38-Xaa39-Xaa40-Ser-Phe-Gln-Gly-Xaa45-Xaa46-Val-Ala-Xaa49-Leu-Tyr-Cys-Phe-Xaa54-Asn-Xaa56-Glu

(10) described (2)-intermediate head-(3) have following array structure [serial ID NO:27]:

RPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLFCNRTFDEYACWPDGEPGS FVNVSCPWYLPWASSVPQGHV YRFCTAEGLW LQKDNSSLPW RDLSECEESK RGERSSPEEQ LLFLY-transition joint-Asn-Xaa2-Ile-His-Xaa5-Asn-Leu-Phe-Xaa9-Ser-Phe-Xaa12-Leu-Xaa14-Xaa13-Xaa15-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Xaa21-Asp-Xaa23-Xaa24-Leu-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa3 2-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43-Leu-Xaa45-Xaa46-Xaa47-Xaa48-Xaa49-Xaa50-Xaa5 1-Xaa52-Xaa53-Xaa54-Xaa55-Xaa56-Xaa57-Xaa58-Met-Gln-Tyr-Xaa62-Xaa63-Xaa64-Ala-Asn-Tyr-Xaa68-Trp-Leu-Leu-Val-Glu-Gly-Xaa75-Tyr-Leu

(11) described (2)-intermediate head-(4) have following array structure [serial ID NO:28]:

RPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLFCNRTFDEYACWPDGEPGS FVNVSCPWYLPWASSVPQGHV YRFCTAEGLW LQKDNSSLPW RDLSECEESK RGERSSPEEQ LLFLY-transition joint-Phe-Xaa2-Leu-Tyr-Xaa5-Xaa6-Ile-Gly-Trp-Gly-Xaa11-Pro-Xaa 13--Leu-Phe-Val-Xaa17-Pro-Trp-Xaa20-Xaa21-Xaa22-Xaa23-Xa a24-Leu-Xaa26-Glu-Xaa28-Xaa29-Xaa30-Cys-Trp-Xaa33-Xaa34-Asn-Xaa36-Asn-Met-Xaa39-Xaa40-Trp-Xaa42-Ile-Xaa44-Arg-Xa a46-Pro-Xaa48-Xaa49-Xaa50-Ala-Ile-Xaa53-Xaa54-Asn-Phe-Xa a57-Ile-Phe-Val-Arg-Xaa62-Xaa63-Xaa64

(12) described (2)-intermediate head-(5) have following array structure [serial ID NO:29]:

RPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLFCNRTFDEYACWPDGEPGS FVNVSCPWYLPWASSVPQGHVYRFCTAEGLWLQKDNSSLPWRDLSECEESKRGERS SPEEQLLFLY-transition joint-Ser-Thr-Leu-Thr-Leu-Ile-Pro-Leu-Leu-Gly-Xaa11-His-Glu-Va l-Xaa15-Phe-Ala-Phe-Val-Xaa20-Asp-Glu-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Leu-Arg-Xaa30-Xaa31-Xaa32-Leu-Phe-Xaa35-Xaa3 6-Leu-Xaa38-Xaa39-Xaa40-Ser-Phe-Gln-Gly-Xaa45-Xaa46-Val-Ala-Xaa49-Leu-Tyr-Cys-Phe-Xaa54-Asn-Xaa56-Glu

(13) described (2)-intermediate head-(6) have following array structure [serial ID NO:30]:

RPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLFCNRTFDEYACWPDGEPGSFVNVSCPWYLPWASSVPQGHVYRFCTAEGLWLQKDNSSLPWRDLSECEESKRGERSSPEEQLLFLY--Asn-Xaa2-Ile-His-Xaa5-Asn-Leu-Phe-Xaa9-Ser-Phe-Xaa12-Leu-Xaa14-Xaa13-Xaa15-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Xaa21-Asp-Xaa23-Xaa24-Leu-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43-Leu-Xaa45-Xaa46-Xaa47-Xaa48-Xaa49-Xaa50-Xaa51-Xaa52-Xaa53-Xaa54-Xaa55-Xaa56-Xaa57-Xaa58-Met-Gln-Tyr-Xaa62-Xaa63-Xaa64-Ala-Asn-Tyr-Xaa68-Trp-Leu-Leu-Val-Glu-Gly-Xaa75-Tyr-Leu--Phe-Xaa2-Leu-Tyr-Xaa5-Xaa6-Ile-Gly-Trp-Gly-Xaa11-Pro-Xaa13-Leu-Phe-Val-Xaa17-Pro-Trp-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Leu-Xaa26-Glu-Xaa28-Xaa29-Xaa30-Cys-Trp-Xaa33-Xaa34-Asn-Xaa36-Asn-Met-Xaa39-Xaa40-Trp-Xaa42-Ile-Xaa44-Arg-Xaa46-Pro-Xaa48-Xaa49-Xaa50-Ala-Ile-Xaa53-Xaa54-Asn-Phe-Xaa57-Ile-Phe-Val-Arg-Xaa62-Xaa63-Xaa64

(14) described (2)-intermediate head-(7) have following array structure [serial ID NO:31]:

RPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLFCNRTFDEYACWPDGEPGSFVNVSCPWYLPWASSVPQGHVYRFCTAEGLWLQKDNSSLPWRDLSECEESKRGERSSPEEQLLFLY--Asn-Xaa2-Ile-His-Xaa5-Asn-Leu-Phe-Xaa9-Ser-Phe-Xaa12-Leu-Xaa14-Xaa13-Xaa15-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Xaa21-Asp-Xaa23-Xaa24-Leu-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43-Leu-Xaa45-Xaa46-Xaa47-Xaa48-Xaa49-Xaa50-Xaa51-Xaa52-Xaa53-Xaa54-Xaa55-Xaa56-Xaa57-Xaa58-Met-Gln-Tyr-Xaa62-Xaa63-Xaa64-Ala-Asn-Tyr-Xaa68-Trp-Leu-Leu-Val-Glu-Gly-Xaa75-Tyr-Leu--Ser-Thr-Leu-Thr-Leu-Ile-Pro-Leu-Leu-Gly-Xaa11-His-Glu-Val-Xaa15-Phe-Ala-Phe-Val-Xaa20-Asp-Glu-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Leu-Arg-Xaa30-Xaa31-Xaa32-Leu-Phe-Xaa35-Xaa36-Leu-Xaa38-Xaa39-Xaa40-Ser-Phe-Gln-Gly-Xaa45-Xaa46-Val-Ala-Xaa49-Leu-Tyr-Cys-Phe-Xaa54-Asn-Xaa56-Glu

(15) described (2)-intermediate head-(8) have following array structure [serial ID NO:32]:

RPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLFCNRTFDEYACWPDGEPGSFVNVSCPWYLPWASSVPQGHVYRFCTAEGLWLQKDNSSLPWRDLSECEESKRGERSSPEEQLLFLY--Phe-Xaa2-Leu-Tyr-Xaa5-Xaa6-Ile-Gly-Trp-Gly-Xaa11-Pro-Xaa13-Leu-Phe-Val-Xaa17-Pro-Trp-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Leu-Xaa26-Glu-Xaa28-Xaa29-Xaa30-Cys-Trp-Xaa33-Xaa34-Asn-Xaa36-Asn-Met-Xaa39-Xaa40-Trp-Xaa42-Ile-Xaa44-Arg-Xaa46-Pro-Xaa48-Xaa49-Xaa50-Ala-Ile-Xaa53-Xaa54-Asn-Phe-Xaa57-Ile-Phe-Val-Arg-Xaa62-Xaa63-Xaa64-Ser-Thr-Leu-Thr-Leu-Ile-Pro-Leu-Leu-Gly-Xaa11-His-Glu-Val-Xaa15-Phe-Ala-Phe-Val-Xaa20-Asp-Glu-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Leu-Arg-Xaa30-Xaa3I-Xaa32-Leu-Phe-Xaa35-Xaa36-Leu-Xaa38-Xaa39-Xaa40-Ser-Phe-Gln-Gly-Xaa45-Xaa46-Val-Ala-Xaa49-Leu-Tyr-Cys-Phe-Xaa54-Asn-Xaa56-Glu

RPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLFCNRTFDEYACWPDGEPGSFVNVSCPWYLPWASSVPQGHVYRFCTAEGLWLQKDNSSLPWRDLSECEESKRGERSSPEEQLLFLY--Phe-Xaa2-Leu-Tyr-Xaa5-Xaa6-Ile-Gly-Trp-Gly-Xaa11-Pro-Xaa13-Leu-Phe-Val-Xaa17-Pro-Trp-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Leu-Xaa26-Glu-Xaa28-Xaa29-Xaa30-Cys-Trp-Xaa33-Xaa34-Asn-Xaa36-Asn-Met-Xaa39-Xaa40-Trp-Xaa42-Ile-Xaa44-Arg-Xaa46-Pro-Xaa48-Xaa49-Xaa50-Ala-Ile-Xaa53-Xaa54-Asn-Phe-Xaa57-Ile-Phe-Val-Arg-Xaa62-Xaa63-Xaa64--Ser-Thr-Leu-Thr-Leu-Ile-Pro-Leu-Leu-Gly-Xaa11-His-Glu-Val-Xaa15-Phe-Ala-Phe-Val-Xaa20-Asp-Glu-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Leu-Arg-Xaa30-Xaa31-Xaa32-Leu-Phe-Xaa35-Xaa36-Leu-Xaa38-Xaa39-Xaa40-Ser-Phe-Gln-Gly-Xaa45-Xaa46-Val-Ala-Xaa49-Leu-Tyr-Cys-Phe-Xaa54-Asn-Xaa56-Glu

(17) described (2)-intermediate head-(9) have following array structure [serial ID NO:33]:

RPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLFCNRTFDEYACWPDGEPGSFVNVSCPWYLPWASSVPQGHVYRFCTAEGLWLQKDNSSLPWRDLSECEESKRGERSSPEEQLLFLY--Asn-Xaa2-Ile-His-Xaa5-Asn-Leu-Phe-Xaa9-Ser-Phe-Xaa12-Leu-Xaa14-Xaa13-Xaa15-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Xaa21-Asp-Xaa23-Xaa24-Leu-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43-Leu-Xaa45-Xaa46-Xaa47-Xaa48-Xaa49-Xaa50-Xaa51-Xaa52-Xaa53-Xaa54-Xaa55-Xaa56-Xaa57-Xaa58-Met-Gln-Tyr-Xaa62-Xaa63-Xaa64-Ala-Asn-Tyr-Xaa68-Trp-Leu-Leu-Val-Glu-Gly-Xaa75-Tyr-Leu--Phe-Xaa2-Leu-Tyr-Xaa5-Xaa6-Ile-Gly-Trp-Gly-Xaa11-Pro-Xaa13-Leu-Phe-Val-Xaa17-Pro-Trp-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Leu-Xaa26-Glu-Xaa28-Xaa29-Xaa30-Cys-Trp-Xaa33-Xaa34-Asn-Xaa36-Asn-Met-Xaa39-Xaa40-Trp-Xaa42-Ile-Xaa44-Arg-Xaa46-Pro-Xaa48-Xaa49-Xaa50-Ala-Ile-Xaa53-Xaa54-Asn-Phe-Xaa57-Ile-Phe-Val-Arg-Xaa62-Xaa63-Xaa64--Ser-Thr-Leu-Thr-Leu-Ile-Pro-Leu-Leu-Gly-Xaa11-His-Glu-Val-Xaa15-Phe-Ala-Phe-Val-Xaa20-Asp-Glu-Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Leu-Arg-Xaa30-Xaa31-Xaa32-Leu-Phe-Xaa35-Xaa36-Leu-Xaa38-Xaa39-Xaa40-Ser-Phe-Gln-Gly-Xaa45-Xaa46-Val-Ala-Xaa49-Leu-Tyr-Cys-Phe-Xaa54-Asn-Xaa56-Glu。

5. the fusion rotein of GLP-1 according to claim 1 is characterized in that being made up of polypeptide A-polypeptide B-peptide C, and wherein, peptide C is from the CH2 of immunoglobulin G while 1Fc, and CH3 section, this Fc section contain following sequence [serial ID NO:34]:

DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK，

Aforementioned polypeptides A, polypeptide B and peptide C can directly connect, and also can connect by the intermediate head in the claim 2.

6.. the fusion rotein of GLP-1 according to claim 1 is characterized in that being made up of polypeptide A-intermediate head-peptide C-intermediate head-polypeptide B, peptide C is the CH2 of immunoglobulin G while 1Fc, CH3 section [serial ID NO:34].

7. one kind is used for the treatment of non insulin dependent diabetes or fat pharmaceutical composition, contains any one fusion rotein among the claim 1-6.

8, the fusion rotein of GLP-1 is used for preparation treatment type i diabetes, type ii diabetes, obesity, glucagonoma of pancreas, airway secretion property disease, metabolic disease, sacroiliitis, osteoporosis, central nervous system disease, restenosis, neurodegenerative disease, kidney depletion, congestive heart failure, nephrotic syndrome, liver cirrhosis, pulmonary edema and hypertension drug.