Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes.

Allosteric Regulation Allosteric Site Amino Acid Motifs Amino Acid Sequence Binding Sites Catechols / metabolism Cryoelectron Microscopy Fenoldopam / chemistry GTP-Binding Protein alpha Subunits, Gs / chemistry HEK293 Cells Humans Ligands Models, Molecular Protein Multimerization Receptors, Dopamine D1 / chemistry Receptors, Dopamine D2 / metabolism Signal Transduction Structural Homology, Protein

DRD1-Gs complex allosteric regulation catecholamine ccryo-EM dopamine receptor noncatechol positive allosteric modulator structure

Journal

Cell

ISSN: 1097-4172

Titre abrégé: Cell

Pays: United States

ID NLM: 0413066

Informations de publication

Date de publication:
18 02 2021

Historique:

received: 14 08 2020

revised: 01 12 2020

accepted: 15 01 2021

pubmed: 12 2 2021

medline: 26 8 2021

entrez: 11 2 2021

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cell.2021.01.028 PMID: 33571432

pubmed: 33571432

pii: S0092-8674(21)00071-4

doi: 10.1016/j.cell.2021.01.028

pii:

doi:

Substances chimiques

Catechols 0

Ligands 0

Receptors, Dopamine D1 0

Receptors, Dopamine D2 0

GTP-Binding Protein alpha Subunits, Gs EC 3.6.5.1

Fenoldopam INU8H2KAWG

catechol LF3AJ089DQ

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

943-956.e18

Subventions

Organisme : NIGMS NIH HHS

ID : R35 GM136387

Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.