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 10-JUN-2026, entry version 105. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 PDB; 9G0M; NMR; -; A=62-86. DR PDB; 9G0N; NMR; -; A=62-86. DR PDB; 9G20; NMR; -; A=62-86. DR PDB; 9G21; NMR; -; A=62-86. DR PDB; 9G22; NMR; -; A=62-86. DR PDB; 9G2N; NMR; -; A=62-86. DR PDB; 9G2O; NMR; -; A=62-86. DR PDB; 9G31; NMR; -; A=62-86. DR PDB; 9G32; NMR; -; A=62-86. DR PDB; 9G5P; NMR; -; A=62-86. 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 PDBsum; 9G0M; -. DR PDBsum; 9G0N; -. DR PDBsum; 9G20; -. DR PDBsum; 9G21; -. DR PDBsum; 9G22; -. DR PDBsum; 9G2N; -. DR PDBsum; 9G2O; -. DR PDBsum; 9G31; -. DR PDBsum; 9G32; -. DR PDBsum; 9G5P; -. DR AlphaFoldDB; P26349; -. DR BMRB; P26349; -. DR EMDB; EMD-23425; -. 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 Gene3D; 6.10.250.590; -; 1. 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" FT HELIX 83..85 FT /evidence="ECO:0007829|PDB:9G20" SQ SEQUENCE 87 AA; 9479 MW; 656BA6E3D87454A2 CRC64; MKIILWLCVF GLFLATLFPI SWQMPVESGL SSEDSASSES FASKIKRHGE GTFTSDLSKQ MEEEAVRLFI EWLKNGGPSS GAPPPSG //