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

doi:10.1038/nature25773

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

Gastroenterology and Hepatology

Research output: Contribution to journal › Article › peer-review

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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 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 language	English (US)
Pages (from-to)	121-125
Number of pages	5
Journal	Nature
Volume	555
Issue number	7694
DOIs	https://doi.org/10.1038/nature25773
State	Published - Mar 1 2018

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Liang, Y. L., Khoshouei, M., Glukhova, A., Furness, S. G. B., Zhao, P., Clydesdale, L., Koole, C., Truong, T. T., Thal, D. M., Lei, S., Radjainia, M., Danev, R., Baumeister, W., Wang, M. W., Miller, L. J., Christopoulos, A., Sexton, P. M., & Wootten, D. (2018). Phase-plate cryo-EM structure of a biased agonistbound human GLP-1 receptor-Gs complex. Nature, 555(7694), 121-125. https://doi.org/10.1038/nature25773

Liang, YL, Khoshouei, M, Glukhova, A, Furness, SGB, Zhao, P, Clydesdale, L, Koole, C, Truong, TT, Thal, DM, Lei, S, Radjainia, M, Danev, R, Baumeister, W, Wang, MW, Miller, LJ, Christopoulos, A, Sexton, PM & Wootten, D 2018, 'Phase-plate cryo-EM structure of a biased agonistbound human GLP-1 receptor-Gs complex', Nature, vol. 555, no. 7694, pp. 121-125. https://doi.org/10.1038/nature25773

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

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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AU - Zhao, Peishen

AU - Clydesdale, Lachlan

AU - Koole, Cassandra

AU - Truong, Tin T.

AU - Thal, David M.

AU - Lei, Saifei

AU - Radjainia, Mazdak

AU - Danev, Radostin

AU - Baumeister, Wolfgang

AU - Wang, Ming Wei

AU - Miller, Laurence J.

AU - Christopoulos, Arthur

AU - Sexton, Patrick M.

AU - Wootten, Denise

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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.

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

Abstract

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