Evolutionarily Conserved Residues at Glucagon-like Peptide-1 (GLP-1) Receptor Core Confer Ligand-induced Receptor Activation
- Authors
- Moon, Mi Jin; Kim, Hee Young; Park, Sumi; Kim, Dong-Kyu; Cho, Eun Bee; Park, Cho Rong; You, Dong-Joo; Hwang, Jong-Ik; Kim, Kyungjin; Choe, Han; Seong, Jae Young
- Issue Date
- 3-2월-2012
- Publisher
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- Keywords
- INSULINOTROPIC POLYPEPTIDE GIP; GASTRIC-INHIBITORY POLYPEPTIDE; TERMINAL EXTRACELLULAR DOMAIN; PROTEIN-COUPLED-RECEPTOR; CRYSTAL-STRUCTURE; CRITICAL DETERMINANTS; PARATHYROID-HORMONE; CHIMERIC RECEPTORS; SECRETIN RECEPTOR; AGONIST BINDING
- Citation
- JOURNAL OF BIOLOGICAL CHEMISTRY, v.287, no.6, pp.3873 - 3884
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF BIOLOGICAL CHEMISTRY
- Volume
- 287
- Number
- 6
- Start Page
- 3873
- End Page
- 3884
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/106078
- DOI
- 10.1074/jbc.M111.276808
- ISSN
- 0021-9258
- 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.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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