Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex.
Nature
; 555(7694): 121-125, 2018 03 01.
Article
em En
| MEDLINE
| ID: mdl-29466332
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, 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Subunidades alfa Gs de Proteínas de Ligação ao GTP
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Microscopia Crioeletrônica
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Peptídeo 1 Semelhante ao Glucagon
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Receptor do Peptídeo Semelhante ao Glucagon 1
Limite:
Humans
Idioma:
En
Revista:
Nature
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Austrália