中国科学院上海药物研究所徐华强等研究人员合作解析人类D1和D2多巴胺受体信号复合物结构。相关论文于2021年2月18日发表在《细胞》杂志上。
研究人员表示，D1和D2多巴胺受体（D1R和D2R）分别通过Gs和Gi发出信号，这是中枢神经系统的主要刺激性和抑制性多巴胺受体。D1R和D2R也??是帕金森氏症、精神分裂症和许多其他神经精神疾病的主要治疗靶标，深入了解其信号传导对于理解多巴胺能药物的治疗和副作用至关重要。
研究人员报道了D1R-Gs和D2R-Gi信号复合物与选择性和非选择性多巴胺激动剂的四种冷冻电镜（cryo-EM）结构，包括两种目前使用的抗帕金森氏病药物，阿扑吗啡和溴隐亭。这些结构以及诱变研究揭示了多巴胺激动剂的保守结合方式、配体选择性背后的独特口袋拓扑、受体活化的构象变化以及G蛋白偶联选择性的潜在结构决定因素。这些结果既提供了对多巴胺信号传导的分子理解，又提供了针对多巴胺能系统药物设计的多个结构模板。
附：英文原文
Title: Structural insights into the human D1 and D2 dopamine receptor signaling complexes
Author: Youwen Zhuang, Peiyu Xu, Chunyou Mao, Lei Wang, Brian Krumm, X. Edward Zhou, Sijie Huang, Heng Liu, Xi Cheng, Xi-Ping Huang, Dan-Dan Shen, Tinghai Xu, Yong-Feng Liu, Yue Wang, Jia Guo, Yi Jiang, Hualiang Jiang, Karsten Melcher, Bryan L. Roth, Yan Zhang, Cheng Zhang, H. Eric Xu
Issue&Volume: 2021/02/18
Abstract: The D1- and D2-dopamine receptors (D1R and D2R), which signal through Gs and Gi, respectively, represent the principal stimulatory and inhibitory dopamine receptorsin the central nervous system. D1R and D2R also represent the main therapeutic targetsfor Parkinson’s disease, schizophrenia, and many other neuropsychiatric disorders,and insight into their signaling is essential for understanding both therapeutic andside 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, includingtwo currently used anti-Parkinson’s disease drugs, apomorphine and bromocriptine.These structures, together with mutagenesis studies, reveal the conserved bindingmode of dopamine agonists, the unique pocket topology underlying ligand selectivity,the conformational changes in receptor activation, and potential structural determinantsfor G protein-coupling selectivity. These results provide both a molecular understandingof dopamine signaling and multiple structural templates for drug design targetingthe dopaminergic system.
DOI: 10.1016/j.cell.2021.01.027
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00070-2