Molecular basis for high-affinity agonist binding in GPCRs.
Science
; 364(6442): 775-778, 2019 05 24.
Article
en En
| MEDLINE
| ID: mdl-31072904
ABSTRACT
G protein-coupled receptors (GPCRs) in the G protein-coupled active state have higher affinity for agonists as compared with when they are in the inactive state, but the molecular basis for this is unclear. We have determined four active-state structures of the ß1-adrenoceptor (ß1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of ß1AR bound to the identical ligands showed a 24 to 42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. This explains the increase in agonist affinity of GPCRs in the active state for a wide range of structurally distinct agonists.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
/
Receptores Acoplados a Proteínas G
/
Agonistas de Receptores Adrenérgicos beta 1
Idioma:
En
Revista:
Science
Año:
2019
Tipo del documento:
Article
País de afiliación:
Reino Unido