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Positive allosteric modulation of a GPCR ternary complex.
Burger, Wessel A C; Draper-Joyce, Christopher J; Valant, Celine; Christopoulos, Arthur; Thal, David M.
Afiliação
  • Burger WAC; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
  • Draper-Joyce CJ; Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
  • Valant C; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
  • Christopoulos A; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
  • Thal DM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Sci Adv ; 10(37): eadp7040, 2024 Sep 13.
Article em En | MEDLINE | ID: mdl-39259792
ABSTRACT
The activation of a G protein-coupled receptor (GPCR) leads to the formation of a ternary complex between agonist, receptor, and G protein that is characterized by high-affinity binding. Allosteric modulators bind to a distinct binding site from the orthosteric agonist and can modulate both the affinity and the efficacy of orthosteric agonists. The influence allosteric modulators have on the high-affinity active state of the GPCR-G protein ternary complex is unknown due to limitations on attempting to characterize this interaction in recombinant whole cell or membrane-based assays. Here, we use the purified M2 muscarinic acetylcholine receptor reconstituted into nanodiscs to show that, once the agonist-bound high-affinity state is promoted by the G protein, positive allosteric modulators stabilize the ternary complex that, in the presence of nucleotides, leads to an enhanced initial rate of signaling. Our results enhance our understanding of how allosteric modulators influence orthosteric ligand signaling and will aid the design of allosteric therapeutics.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ligação Proteica / Receptores Acoplados a Proteínas G / Receptor Muscarínico M2 Limite: Humans Idioma: En Revista: Sci Adv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Austrália País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ligação Proteica / Receptores Acoplados a Proteínas G / Receptor Muscarínico M2 Limite: Humans Idioma: En Revista: Sci Adv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Austrália País de publicação: Estados Unidos