Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery

Kaleeckal G Harikumar, Denise L Wootten, Delia I Pinon, Cassandra R Koole, Alicja M Ball, Sebastian GB Furness, Bim Graham, Maoqing Dong, Arthur Christopoulos, Laurence J Miller, Patrick M Sexton

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41 Citations (Scopus)

Abstract

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 on receptor signaling. There was
Original languageEnglish
Pages (from-to)18607 - 18612
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number45
DOIs
Publication statusPublished - 2012

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