近日，中国科学院上海药物研究所徐华强等研究人员合作揭示人类多巴胺受体系统的结构基因组学。相关论文于2023年5月23日在线发表在《细胞研究》杂志上。

研究人员表示，多巴胺能系统，包括五个多巴胺受体（D1R至D5R），在中枢神经系统（CNS）中发挥着重要作用；激活多巴胺受体的配体已被用于治疗许多神经精神疾病，包括帕金森病（PD）和精神分裂症。

研究人员报告了所有五个亚型的人类多巴胺受体与G蛋白复合并与泛激动剂罗替戈汀结合的冷冻电镜结构。罗替戈汀被用于治疗帕金森病和不宁腿综合征。这些结构揭示了不同多巴胺受体对罗替戈汀的识别基础。结构分析与功能检测一起阐明了配体多药性和选择性的决定因素。这些结构还揭示了多巴胺受体的激活机制、五个受体亚型的独特结构特征以及G蛋白偶联特异性的基础。这项工作为合理设计特定配体来治疗针对多巴胺能系统的中枢神经疾病提供了一套全面的结构模板。

附：英文原文

Title: Structural genomics of the human dopamine receptor system

Author: Xu, Peiyu, Huang, Sijie, Krumm, Brian E., Zhuang, Youwen, Mao, Chunyou, Zhang, Yumu, Wang, Yue, Huang, Xi-Ping, Liu, Yong-Feng, He, Xinheng, Li, Huadong, Yin, Wanchao, Jiang, Yi, Zhang, Yan, Roth, Bryan L., Xu, H. Eric

Issue&Volume: 2023-05-23

Abstract: The dopaminergic system, including five dopamine receptors (D1R to D5R), plays essential roles in the central nervous system (CNS); and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders, including Parkinson’s Disease (PD) and schizophrenia. Here, we report cryo-EM structures of all five subtypes of human dopamine receptors in complex with G protein and bound to the pan-agonist, rotigotine, which is used to treat PD and restless legs syndrome. The structures reveal the basis of rotigotine recognition in different dopamine receptors. Structural analysis together with functional assays illuminate determinants of ligand polypharmacology and selectivity. The structures also uncover the mechanisms of dopamine receptor activation, unique structural features among the five receptor subtypes, and the basis of G protein coupling specificity. Our work provides a comprehensive set of structural templates for the rational design of specific ligands to treat CNS diseases targeting the dopaminergic system.

DOI: 10.1038/s41422-023-00808-0

Source: https://www.nature.com/articles/s41422-023-00808-0