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Phase-plate cryo-EM structure of a biased agonist-bound 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.
Nature; 555(7694): 121-125, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29466332
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, 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 Gαs protein. Our structure provides insights into the molecular basis of biased agonism.
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