Structures of the human dopamine D3 receptor-Gi complexes

• Published in: Molecular cell 2021-03, Vol.81 (6), p.1147-1159.e4
• Main Authors: Xu, Peiyu, Huang, Sijie, Mao, Chunyou, Krumm, Brian E., Zhou, X. Edward, Tan, Yangxia, Huang, Xi-Ping, Liu, Yongfeng, Shen, Dan-Dan, Jiang, Yi, Yu, Xuekui, Jiang, Hualiang, Melcher, Karsten, Roth, Bryan L., Cheng, Xi, Zhang, Yan, Xu, H. Eric
• Format: Article
• Language: English
• Subjects: cryo-EM structure; D3R; dopamine receptor; dopamine receptor activation; G protein selectivity; GPCR; ligand selectivity; Parkinson’s disease; pramipexole; signaling complex
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.01.003

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. [Display omitted] •Structures of dopamine receptor D3R with agonists pramipexole and PD128907•Different binding modes of agonists with similar pharmacological properties to D3R•Conformational changes associated with D3R activation and selective G protein coupling•Selective mechanism of agonists to D3R versus D2R and D4R Xu et al. report two cryo-EM structures of dopamine receptor D3R bound to Gi protein and D3R-selective agonists, PD128907 and the Parkinson’s disease drug pramipexole. The structures reveal the basis of ligand selectivity, ligand-induced D3R activation, and selective Gi coupling by D3R.