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

Research output: Contribution to journalArticleResearchpeer-review

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
Volume109
Issue number45
DOIs
Publication statusPublished - 2012

Cite this

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title = "Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery",
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",
author = "Harikumar, {Kaleeckal G} and Wootten, {Denise L} and Pinon, {Delia I} and Koole, {Cassandra R} and Ball, {Alicja M} and Furness, {Sebastian GB} and Bim Graham and Maoqing Dong and Arthur Christopoulos and Miller, {Laurence J} and Sexton, {Patrick M}",
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language = "English",
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journal = "Proceedings of the National Academy of Sciences of the United States of America",
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Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery. / Harikumar, Kaleeckal G; Wootten, Denise L; Pinon, Delia I; Koole, Cassandra R; Ball, Alicja M; Furness, Sebastian GB; Graham, Bim; Dong, Maoqing; Christopoulos, Arthur; Miller, Laurence J; Sexton, Patrick M.

In: Proceedings of the National Academy of Sciences, Vol. 109, No. 45, 2012, p. 18607 - 18612.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

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AU - Harikumar, Kaleeckal G

AU - Wootten, Denise L

AU - Pinon, Delia I

AU - Koole, Cassandra R

AU - Ball, Alicja M

AU - Furness, Sebastian GB

AU - Graham, Bim

AU - Dong, Maoqing

AU - Christopoulos, Arthur

AU - Miller, Laurence J

AU - Sexton, Patrick M

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AB - 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

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