Journal article

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

Yi-Lynn Liang, Maryam Khoshouei, Alisa Glukhova, Sebastian GB 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

Nature | NATURE PUBLISHING GROUP | Published : 2018

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 Gαs 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..

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Grants

Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by NHMRC


Awarded by Strategic Priority Research Program of the Chinese Academy of Sciences


Awarded by Shanghai Science and Technology Development Fund


Funding Acknowledgements

The work was supported by the Monash University Ramaciotti Centre for Cryo-Electron Microscopy, the National Health and Medical Research Council of Australia (NHMRC) project grants (1061044, 1065410, 1120919 and 1126857), NHMRC program grant (1055134), Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020347) and Shanghai Science and Technology Development Fund (15DZ2291600). P.M.S., A.C., D.W. and C.K. are NHMRC Principal Research, Senior Principal Research, Career Development and CJ Martin Fellows, respectively. S.L. received the Postgraduate Overseas Study Fellowship from CAS. We thank J. Plitzko, G. Christopoulos, V. Julita, J. Michaelis, X. Zhang, P. Thompson and M. Liu for assay and technical support and B. Kobilka for technical advice and comments on the manuscript.