ID   EXE4_HELSU              Reviewed;          87 AA.
AC   P26349;
DT   01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
DT   15-JUL-1998, sequence version 2.
DT   25-MAY-2022, entry version 101.
DE   RecName: Full=Exendin-4;
DE   AltName: INN=Exenatide;
DE   Flags: Precursor;
OS   Heloderma suspectum (Gila monster).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC   Anguimorpha; Neoanguimorpha; Helodermatidae; Heloderma.
OX   NCBI_TaxID=8554;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=9020121; DOI=10.1074/jbc.272.7.4108;
RA   Chen Y.E., Drucker D.J.;
RT   "Tissue-specific expression of unique mRNAs that encode proglucagon-derived
RT   peptides or exendin 4 in the lizard.";
RL   J. Biol. Chem. 272:4108-4115(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=9545315; DOI=10.1074/jbc.273.16.9778;
RA   Pohl M., Wank S.A.;
RT   "Molecular cloning of the helodermin and exendin-4 cDNAs in the lizard.
RT   Relationship to vasoactive intestinal polypeptide/pituitary adenylate
RT   cyclase activating polypeptide and glucagon-like peptide 1 and evidence
RT   against the existence of mammalian homologues.";
RL   J. Biol. Chem. 273:9778-9784(1998).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 48-86, AND MASS
RP   SPECTROMETRY.
RC   TISSUE=Venom;
RX   PubMed=16386282; DOI=10.1016/j.toxicon.2005.11.004;
RA   Chen T., Kwok H., Ivanyi C., Shaw C.;
RT   "Isolation and cloning of exendin precursor cDNAs from single samples of
RT   venom from the Mexican beaded lizard (Heloderma horridum) and the Gila
RT   monster (Heloderma suspectum).";
RL   Toxicon 47:288-295(2006).
RN   [4]
RP   PROTEIN SEQUENCE OF 48-86, AND AMIDATION AT SER-86.
RC   TISSUE=Venom;
RX   PubMed=1313797; DOI=10.1016/s0021-9258(18)42531-8;
RA   Eng J., Kleinman W.A., Singh L., Singh G., Raufman J.-P.;
RT   "Isolation and characterization of exendin-4, an exendin-3 analogue, from
RT   Heloderma suspectum venom. Further evidence for an exendin receptor on
RT   dispersed acini from guinea pig pancreas.";
RL   J. Biol. Chem. 267:7402-7405(1992).
RN   [5]
RP   FUNCTION.
RX   PubMed=8405712; DOI=10.2337/diab.42.11.1678;
RA   Thorens B., Porret A., Buehler L., Deng S., Morel P., Widmann C.;
RT   "Cloning and functional expression of the human islet GLP-1 receptor.
RT   Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist
RT   of the receptor.";
RL   Diabetes 42:1678-1682(1993).
RN   [6]
RP   SYNTHESIS OF 48-86, AND FUNCTION.
RX   PubMed=19837656; DOI=10.1093/molbev/msp251;
RA   Fry B.G., Roelants K., Winter K., Hodgson W.C., Griesman L., Kwok H.F.,
RA   Scanlon D., Karas J., Shaw C., Wong L., Norman J.A.;
RT   "Novel venom proteins produced by differential domain-expression strategies
RT   in beaded lizards and gila monsters (genus Heloderma).";
RL   Mol. Biol. Evol. 27:395-407(2010).
RN   [7]
RP   REVIEW, AND PHARMACEUTICAL.
RX   PubMed=21194543; DOI=10.1016/j.toxicon.2010.12.016;
RA   Furman B.L.;
RT   "The development of Byetta (exenatide) from the venom of the Gila monster
RT   as an anti-diabetic agent.";
RL   Toxicon 59:464-471(2012).
RN   [8]
RP   REVIEW, AND PHARMACEUTICAL.
RX   PubMed=25018644; DOI=10.2147/dmso.s35331;
RA   Mann K.V., Raskin P.;
RT   "Exenatide extended-release: a once weekly treatment for patients with type
RT   2 diabetes.";
RL   Diabetes Metab. Syndr. Obes. 7:229-239(2014).
RN   [9]
RP   STRUCTURE BY NMR OF 48-86.
RX   PubMed=11683627; DOI=10.1021/bi010902s;
RA   Neidigh J.W., Fesinmeyer R.M., Prickett K.S., Andersen N.H.;
RT   "Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the
RT   solution and micelle-associated states.";
RL   Biochemistry 40:13188-13200(2001).
CC   -!- FUNCTION: Venom protein that mimics the incretin hormone glucagon-like
CC       peptide 1 (GLP-1). It stimulates insulin synthesis and secretion,
CC       protects against beta-cell apoptosis in response to different insults,
CC       and promotes beta-cell proliferation. It also promotes satiety, reduces
CC       food intake, reduces fat deposition, reduces body weight and inhibits
CC       gastric emptying. Interacts with GLP-1 receptor (GLP1R). Induces
CC       hypotension that is mediated by relaxation of cardiac smooth muscle.
CC       {ECO:0000269|PubMed:19837656, ECO:0000269|PubMed:8405712}.
CC   -!- SUBCELLULAR LOCATION: Secreted.
CC   -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC   -!- MASS SPECTROMETRY: Mass=4186.02; Method=MALDI;
CC       Evidence={ECO:0000269|PubMed:16386282};
CC   -!- PHARMACEUTICAL: Available under the name Byetta and Bydureon (extended-
CC       release exenatide) (Amylin Pharmaceuticals). Used for the treatment of
CC       type 2 diabetes. Enhances insulin secretion in response to elevated
CC       plasma glucose levels.
CC   -!- SIMILARITY: Belongs to the glucagon family. {ECO:0000305}.
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DR   EMBL; U77613; AAB51130.1; -; mRNA.
DR   PIR; A42486; HWGH4G.
DR   PDB; 1JRJ; NMR; -; A=48-86.
DR   PDB; 2MJ9; NMR; -; A=48-86.
DR   PDB; 2NAV; NMR; -; A=48-56.
DR   PDB; 2NAW; NMR; -; A=48-77.
DR   PDB; 3C59; X-ray; 2.30 A; B=56-86.
DR   PDB; 3C5T; X-ray; 2.10 A; B=56-86.
DR   PDB; 5NIQ; NMR; -; A=48-86.
DR   PDB; 5OTT; X-ray; 1.92 A; B=48-86.
DR   PDB; 6GDZ; NMR; -; A=48-86.
DR   PDB; 6GE2; NMR; -; A=48-86.
DR   PDB; 7LLL; EM; 3.70 A; P=48-86.
DR   PDB; 7MLL; NMR; -; A=48-86.
DR   PDBsum; 1JRJ; -.
DR   PDBsum; 2MJ9; -.
DR   PDBsum; 2NAV; -.
DR   PDBsum; 2NAW; -.
DR   PDBsum; 3C59; -.
DR   PDBsum; 3C5T; -.
DR   PDBsum; 5NIQ; -.
DR   PDBsum; 5OTT; -.
DR   PDBsum; 6GDZ; -.
DR   PDBsum; 6GE2; -.
DR   PDBsum; 7LLL; -.
DR   PDBsum; 7MLL; -.
DR   AlphaFoldDB; P26349; -.
DR   BMRB; P26349; -.
DR   SMR; P26349; -.
DR   Allergome; 11965; Hel su Exenatide.
DR   EvolutionaryTrace; P26349; -.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0005179; F:hormone activity; IEA:InterPro.
DR   GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR   GO; GO:0008217; P:regulation of blood pressure; IEA:UniProtKB-KW.
DR   InterPro; IPR000532; Glucagon_GIP_secretin_VIP.
DR   Pfam; PF00123; Hormone_2; 1.
DR   SMART; SM00070; GLUCA; 1.
DR   PROSITE; PS00260; GLUCAGON; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Amidation; Cleavage on pair of basic residues;
KW   Direct protein sequencing; G-protein coupled receptor impairing toxin;
KW   Hypotensive agent; Pharmaceutical; Secreted; Signal; Toxin.
FT   SIGNAL          1..23
FT                   /evidence="ECO:0000255"
FT   PROPEP          24..45
FT                   /id="PRO_0000011421"
FT   PEPTIDE         48..86
FT                   /note="Exendin-4"
FT                   /id="PRO_0000011422"
FT   MOD_RES         86
FT                   /note="Serine amide"
FT                   /evidence="ECO:0000269|PubMed:1313797"
FT   CONFLICT        13
FT                   /note="F -> G (in Ref. 2; no nucleotide entry)"
FT                   /evidence="ECO:0000305"
FT   STRAND          54..56
FT                   /evidence="ECO:0007829|PDB:7MLL"
FT   HELIX           57..74
FT                   /evidence="ECO:0007829|PDB:5OTT"
FT   HELIX           77..79
FT                   /evidence="ECO:0007829|PDB:5OTT"
FT   STRAND          80..82
FT                   /evidence="ECO:0007829|PDB:1JRJ"
SQ   SEQUENCE   87 AA;  9479 MW;  656BA6E3D87454A2 CRC64;
     MKIILWLCVF GLFLATLFPI SWQMPVESGL SSEDSASSES FASKIKRHGE GTFTSDLSKQ
     MEEEAVRLFI EWLKNGGPSS GAPPPSG