Phase-plate cryo-EM structure of a biased agonistbound human GLP-1 receptor-Gs complex

Yi Lynn Liang, Maryam Khoshouei, Alisa Glukhova, Sebastian G.B. Furness, Peishen Zhao, Lachlan Clydesdale, Cassandra Koole, Tin T. Truong, David M. Thal, Saifei Lei, Mazdak Radjainia, Radostin Danev, Wolfgang Baumeister, Ming Wei Wang, Laurence J. Miller, Arthur Christopoulos, Patrick M. Sexton, Denise Wootten

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity. Endogenous and mimetic GLP-1 peptides exhibit biased agonism - a difference in functional selectivity - that may provide improved therapeutic outcomes. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a Gα(s) heterotrimer, determined at a global resolution of 3.3 Å. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-bound structure and previous GLP-1-bound GLP-1 receptor structure. At the intracellular face, there was a six-degree difference in the angle of the Gαs-α5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the Gα(s) protein. Our structure provides insights into the molecular basis of biased agonism.

Original languageEnglish
Pages (from-to)121-125
Number of pages5
JournalNature
Volume555
Issue number7694
DOIs
Publication statusPublished - 1 Mar 2018

Cite this

Liang, Yi Lynn ; Khoshouei, Maryam ; Glukhova, Alisa ; Furness, Sebastian G.B. ; Zhao, Peishen ; Clydesdale, Lachlan ; Koole, Cassandra ; Truong, Tin T. ; Thal, David M. ; Lei, Saifei ; Radjainia, Mazdak ; Danev, Radostin ; Baumeister, Wolfgang ; Wang, Ming Wei ; Miller, Laurence J. ; Christopoulos, Arthur ; Sexton, Patrick M. ; Wootten, Denise. / Phase-plate cryo-EM structure of a biased agonistbound human GLP-1 receptor-Gs complex. In: Nature. 2018 ; Vol. 555, No. 7694. pp. 121-125.
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abstract = "The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity. Endogenous and mimetic GLP-1 peptides exhibit biased agonism - a difference in functional selectivity - that may provide improved therapeutic outcomes. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a Gα(s) heterotrimer, determined at a global resolution of 3.3 {\AA}. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-bound structure and previous GLP-1-bound GLP-1 receptor structure. At the intracellular face, there was a six-degree difference in the angle of the Gαs-α5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the Gα(s) protein. Our structure provides insights into the molecular basis of biased agonism.",
author = "Liang, {Yi Lynn} and Maryam Khoshouei and Alisa Glukhova and Furness, {Sebastian G.B.} and Peishen Zhao and Lachlan Clydesdale and Cassandra Koole and Truong, {Tin T.} and Thal, {David M.} and Saifei Lei and Mazdak Radjainia and Radostin Danev and Wolfgang Baumeister and Wang, {Ming Wei} and Miller, {Laurence J.} and Arthur Christopoulos and Sexton, {Patrick M.} and Denise Wootten",
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Phase-plate cryo-EM structure of a biased agonistbound human GLP-1 receptor-Gs complex. / Liang, Yi Lynn; Khoshouei, Maryam; Glukhova, Alisa; Furness, Sebastian G.B.; Zhao, Peishen; Clydesdale, Lachlan; Koole, Cassandra; Truong, Tin T.; Thal, David M.; Lei, Saifei; Radjainia, Mazdak; Danev, Radostin; Baumeister, Wolfgang; Wang, Ming Wei; Miller, Laurence J.; Christopoulos, Arthur; Sexton, Patrick M.; Wootten, Denise.

In: Nature, Vol. 555, No. 7694, 01.03.2018, p. 121-125.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Khoshouei, Maryam

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AU - Zhao, Peishen

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AU - Baumeister, Wolfgang

AU - Wang, Ming Wei

AU - Miller, Laurence J.

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N2 - The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity. Endogenous and mimetic GLP-1 peptides exhibit biased agonism - a difference in functional selectivity - that may provide improved therapeutic outcomes. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a Gα(s) heterotrimer, determined at a global resolution of 3.3 Å. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-bound structure and previous GLP-1-bound GLP-1 receptor structure. At the intracellular face, there was a six-degree difference in the angle of the Gαs-α5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the Gα(s) protein. Our structure provides insights into the molecular basis of biased agonism.

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