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 journalArticle

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

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Glucagon-Like Peptide 1
GTP-Binding Proteins
Peptides
G-Protein-Coupled Receptors
Type 2 Diabetes Mellitus
Obesity
Glucagon-Like Peptide-1 Receptor
Proteins
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Liang, Y. L., Khoshouei, M., Glukhova, A., Furness, S. G. B., Zhao, P., Clydesdale, L., ... 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

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 journalArticle

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
Liang YL, Khoshouei M, Glukhova A, Furness SGB, Zhao P, Clydesdale L et al. Phase-plate cryo-EM structure of a biased agonistbound human GLP-1 receptor-Gs complex. Nature. 2018 Mar 1;555(7694):121-125. https://doi.org/10.1038/nature25773
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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