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The dopamine system, including five dopamine receptors (D1R-D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders. Here, we report two cryo-EM structures of human D3R in complex with an inhibitory G protein and bound to the D3R-selective agonists PD128907 and pramipexole, the latter of which is used to treat patients with Parkinson's disease. The structures reveal agonist binding modes distinct from the antagonist-bound D3R structure and conformational signatures for ligand-induced receptor activation. Mutagenesis and homology modeling illuminate determinants of ligand specificity across dopamine receptors and the mechanisms for Gi protein coupling. Collectively our work reveals the basis of agonist binding and ligand-induced receptor activation and provides structural templates for designing specific ligands to treat CNS diseases targeting the dopaminergic system. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Peiyu Xu, Sijie Huang, Chunyou Mao, Brian E Krumm, X Edward Zhou, Yangxia Tan, Xi-Ping Huang, Yongfeng Liu, Dan-Dan Shen, Yi Jiang, Xuekui Yu, Hualiang Jiang, Karsten Melcher, Bryan L Roth, Xi Cheng, Yan Zhang, H Eric Xu. Structures of the human dopamine D3 receptor-Gi complexes. Molecular cell. 2021 Mar 18;81(6):1147-1159.e4

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PMID: 33548201

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