SIGNAL TRANSDUCTION. Structural basis for nucleotide exchange in heterotrimeric G proteins.
Science
; 348(6241): 1361-5, 2015 Jun 19.
Article
en En
| MEDLINE
| ID: mdl-26089515
ABSTRACT
G protein-coupled receptors (GPCRs) relay diverse extracellular signals into cells by catalyzing nucleotide release from heterotrimeric G proteins, but the mechanism underlying this quintessential molecular signaling event has remained unclear. Here we use atomic-level simulations to elucidate the nucleotide-release mechanism. We find that the G protein α subunit Ras and helical domains-previously observed to separate widely upon receptor binding to expose the nucleotide-binding site-separate spontaneously and frequently even in the absence of a receptor. Domain separation is necessary but not sufficient for rapid nucleotide release. Rather, receptors catalyze nucleotide release by favoring an internal structural rearrangement of the Ras domain that weakens its nucleotide affinity. We use double electron-electron resonance spectroscopy and protein engineering to confirm predictions of our computationally determined mechanism.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Subunidades alfa de la Proteína de Unión al GTP Gi-Go
/
Subunidades alfa de la Proteína de Unión al GTP Gs
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Factores de Intercambio de Guanina Nucleótido
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Receptores Acoplados a Proteínas G
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Science
Año:
2015
Tipo del documento:
Article