7CRH

Cryo-EM structure of SKF83959 bound dopamine receptor DRD1-Gs signaling complex

Summary for 7CRH

• Entry DOI: 10.2210/pdb7crh/pdb
• EMDB information: 30452
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: cell signaling, cell cycle
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 159355.56

Authors

Yan, W.,Shao, Z.H. (deposition date: 2020-08-13, release date: 2021-03-03)

Primary citation

Xiao, P.,Yan, W.,Gou, L.,Zhong, Y.N.,Kong, L.,Wu, C.,Wen, X.,Yuan, Y.,Cao, S.,Qu, C.,Yang, X.,Yang, C.C.,Xia, A.,Hu, Z.,Zhang, Q.,He, Y.H.,Zhang, D.L.,Zhang, C.,Hou, G.H.,Liu, H.,Zhu, L.,Fu, P.,Yang, S.,Rosenbaum, D.M.,Sun, J.P.,Du, Y.,Zhang, L.,Yu, X.,Shao, Z.
Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes.
Cell, 184:943-956.e18, 2021

PubMed 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.

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

Experimental method

ELECTRON MICROSCOPY (3.3 Å)