title: Ligand binding pocket formed by evolutionarily conserved residues in the glucagon-like peptide-1 (GLP-1) receptor core domain.
abstract: Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis through its receptor GLP1R. Due to its multiple beneficial effects, GLP-1 has gained great attention for treatment of type 2 diabetes and obesity. However, little is known about the molecular mechanism underlying the interaction of GLP-1 with the heptahelical core domain of GLP1R conferring high affinity ligand binding and ligand-induced receptor activation. Here, using chimeric and point-mutated GLP1R, we determined that the evolutionarily conserved amino acid residue Arg(380) flanked by hydrophobic Leu(379) and Phe(381) in extracellular loop 3 (ECL3) may have an interaction with Asp(9) and Gly(4) of the GLP-1 peptide. The molecular modeling study showed that Ile(196) at transmembrane helix 2, Met(233) at ECL1, and Asn(302) at ECL2 of GLP1R have contacts with His(1) and Thr(7) of GLP-1. This study may shed light on the mechanism underlying high affinity interaction between the ligand and the binding pocket that is formed by these conserved residues in the GLP1R core domain.
authors.affiliation: From the Graduate School of Medicine, Korea University, Seoul 136-705, Republic of Korea.
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Moon
authors.affiliation: From the Graduate School of Medicine, Korea University, Seoul 136-705, Republic of Korea.
authors.forename: Yoo-Na
authors.initials: YN
authors.lastname: Lee
authors.affiliation: From the Graduate School of Medicine, Korea University, Seoul 136-705, Republic of Korea.
authors.forename: Sumi
authors.initials: S
authors.lastname: Park
authors.affiliation: From the Graduate School of Medicine, Korea University, Seoul 136-705, Republic of Korea.
authors.forename: Arfaxad
authors.initials: A
authors.lastname: Reyes-Alcaraz
authors.affiliation: From the Graduate School of Medicine, Korea University, Seoul 136-705, Republic of Korea.
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Hwang
authors.affiliation: Mammal Research Institute, Department of Zoology and Entomology, University of Pretoria, Pretoria 0028, Medical Research Council Receptor Biology Unit, and University of Cape Town, Cape Town 7925, South Africa, and Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH164TJ, Scotland, and.
authors.forename: Robert Peter
authors.initials: RP
authors.lastname: Millar
authors.affiliation: Department of Physiology and Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul 138-736, Korea hchoe@ulsan.ac.kr.
authors.forename: Han
authors.initials: H
authors.lastname: Choe
authors.affiliation: From the Graduate School of Medicine, Korea University, Seoul 136-705, Republic of Korea, jyseong@korea.ac.kr.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics; D019143:Evolution, Molecular; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018027:Receptors, Glucagon / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D000596:Amino Acids; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D008024:Ligands; D010455:Peptides; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1
keywords: Diabetes; Evolution; G Protein-coupled Receptor (GPCR); GLP-1; GLP1R; Ligand Selectivity; Molecular Modeling; Signaling