Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes.
Cell
; 184(4): 943-956.e18, 2021 02 18.
Article
en En
| MEDLINE
| ID: mdl-33571432
ABSTRACT
Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five cryoelectron microscopy (cryo-EM) structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer in complex with three catechol-based agonists, a non-catechol agonist, and a positive allosteric modulator for endogenous dopamine. These structures revealed that a polar interaction network is essential for catecholamine-like agonist recognition, whereas specific motifs in the extended binding pocket were responsible for discriminating D1- from D2-like receptors. Moreover, allosteric binding at a distinct inner surface pocket improved the activity of DRD1 by stabilizing endogenous dopamine interaction at the orthosteric site. DRD1-Gs interface revealed key features that serve as determinants for G protein coupling. Together, our study provides a structural understanding of the ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Receptores de Dopamina D1
/
Subunidades alfa de la Proteína de Unión al GTP Gs
Límite:
Humans
Idioma:
En
Revista:
Cell
Año:
2021
Tipo del documento:
Article