期刊
CELL
卷 184, 期 4, 页码 943-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2021.01.028
关键词
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资金
- Science and Technology Department of Sichuan Province [2020YJ0208]
- National Key R&D Program of China [2019YFA0508800]
- National Science Fund for Excellent Young Scholars [81822008, 11922410]
- National Science Fund for Distinguished Young Scholars [81825022]
- National Natural Science Foundation of China [31972916, 31971195]
- Shandong University Youth Interdisciplinary Science Innovation Group [2020QNQT002]
- National Institutes of Health [R35GM136387]
Dopamine receptors, includingD1- and D2-like receptors, are key therapeutic targets in various neurological syndromes, cardiovascular, and kidney diseases. This study presents cryo-EM structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer, providing insights into ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1.
Dopamine receptors, includingD1- 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.
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