title: Evolutionarily conserved residues at glucagon-like peptide-1 (GLP-1) receptor core confer ligand-induced receptor activation.
abstract: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play important roles in insulin secretion through their receptors, GLP1R and GIPR. Although GLP-1 and GIP are attractive candidates for treatment of type 2 diabetes and obesity, little is known regarding the molecular interaction of these peptides with the heptahelical core domain of their receptors. These core domains are important not only for specific ligand binding but also for ligand-induced receptor activation. Here, using chimeric and point-mutated GLP1R/GIPR, we determined that evolutionarily conserved amino acid residues such as Ile(196) at transmembrane helix 2, Leu(232) and Met(233) at extracellular loop 1, and Asn(302) at extracellular loop 2 of GLP1R are responsible for interaction with ligand and receptor activation. Application of chimeric GLP-1/GIP peptides together with molecular modeling suggests that His(1) of GLP-1 interacts with Asn(302) of GLP1R and that Thr(7) of GLP-1 has close contact with a binding pocket formed by Ile(196), Leu(232), and Met(233) of GLP1R. This study may provide critical clues for the development of peptide and/or nonpeptide agonists acting at GLP1R.
authors: Graduate School of Medicine, Korea University, Seoul 136-705, Korea.
authors: Mi Jin
authors: MJ
authors: Moon
authors: Hee Young
authors: HY
authors: Kim
authors: Sumi
authors: S
authors: Park
authors: Dong-Kyu
authors: DK
authors: Kim
authors: Eun Bee
authors: EB
authors: Cho
authors: Cho Rong
authors: CR
authors: Park
authors: Dong-Joo
authors: DJ
authors: You
authors: Jong-Ik
authors: JI
authors: Hwang
authors: Kyungjin
authors: K
authors: Kim
authors: Han
authors: H
authors: Choe
authors: Jae Young
authors: JY
authors: Seong
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018027:Receptors, Glucagon / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; C041086:gastric inhibitory polypeptide receptor