biostudies-literatureHarikumar KGNIDDK NIH HHS18607-12https://www.ebi.ac.uk/biostudies/studies/S-EPMC3494884biostudies-literatureUnknown109(45)The glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH(2) but has selective effects Proceedings of the National Academy of Sciences of the United States of AmericaGlucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery.PMC3494884R01 DK046577DK46577.R56 DK046577Pinon DISexton PMMiller LJGraham BWootten DDong MBall AMKoole CFurness SGChristopoulos AHarikumar KGfalseGlucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery.The glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH(2) but has selective effects 2012-01-01T00:00:00Z2012 Nov2025-04-04T10:11:35.689Z2019-03-27T01:00:17ZS-EPMC34948842309103410.1073/pnas.1205227109