多巴胺
多巴胺能
多巴胺受体D2
生物
多巴胺受体
信号转导
神经科学
D1样受体
D2样受体
多巴胺受体D1
受体
溴隐亭
细胞生物学
药理学
多巴胺受体D3
生物化学
激素
催乳素
作者
Yahui Zhuang,Peiyu Xu,Chunyou Mao,Lei Wang,Brian E. Krumm,Xuemei Zhou,Sijie Huang,Heng Liu,Xi Cheng,Xi‐Ping Huang,Dan‐Dan Shen,Tianyuan Xu,Yongfeng Liu,Yue Wang,Jia Guo,Yi Jiang,Hualiang Jiang,Karsten Melcher,Bryan L. Roth,Yan Zhang,Cheng Zhang,Hao Xu
出处
期刊:Cell
[Elsevier]
日期:2021-02-01
卷期号:184 (4): 931-942.e18
被引量:135
标识
DOI:10.1016/j.cell.2021.01.027
摘要
The D1- and D2-dopamine receptors (D1R and D2R), which signal through Gs and Gi, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson’s disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-Gs and D2R-Gi signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson’s disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.
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