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Xiao, Peng; Yan, Wei; Gou, Lu; Zhong, Ya-Ni; Kong, Liangliang; Wu, Chao; Wen, Xin; Yuan, Yuan; Cao, Sheng; Qu, Changxiu; Yang, Xin; Yang, Chuan-Cheng; Xia, Anjie; Hu, Zhenquan; Zhang, Qianqian; He, Yong-Hao; Zhang, Dao-Lai; Zhang, Chao; Hou, Gui-Hua; Liu, Huanxiang; Zhu, Lizhe; Fu, Ping; Yang, Shengyong; Rosenbaum, Daniel M.; Sun, Jin-Peng; Du, Yang; Zhang, Lei; Yu, Xiao; Shao, Zhenhua
Cell, 02/2021, Volume: 184, Issue: 4Journal Article
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. Display omitted •Structures of DRD1-Gs in complex with catechol-based and non-catechol agonists•Key polar interaction network is involved in DRD1 activation•Specific features for agonists interaction and Gs coupling of DRD1 are determined•Structure of DRD1-Gs complexed with dopamine and positive allosteric modulator•Structural basis of allosteric regulation of DRD1 by LY3154207 is investigated The cryo-EM structures of DRD1 coupled to its G protein, in complex with important agonists, elucidates the mechanism of G-protein-coupled selectivity and will facilitate future drug discovery and design.
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