A combined activation mechanism for the glucagon receptor.
Proc Natl Acad Sci U S A
; 117(27): 15414-15422, 2020 07 07.
Article
em En
| MEDLINE
| ID: mdl-32571939
ABSTRACT
We report on a combined activation mechanism for a class B G-protein-coupled receptor (GPCR), the glucagon receptor. By computing the conformational free-energy landscape associated with the activation of the receptor-agonist complex and comparing it with that obtained with the ternary complex (receptor-agonist-G protein) we show that the agonist stabilizes the receptor in a preactivated complex, which is then fully activated upon binding of the G protein. The proposed mechanism contrasts with the generally assumed GPCR activation mechanism, which proceeds through an opening of the intracellular region allosterically elicited by the binding of the agonist. The mechanism found here is consistent with electron cryo-microscopy structural data and might be general for class B GPCRs. It also helps us to understand the mode of action of the numerous allosteric antagonists of this important drug target.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Receptores de Glucagon
/
Proteínas de Ligação ao GTP
/
Domínios Proteicos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Reino Unido