Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China.
Mol Cell. 2021 Mar 18;81(6):1147-1159.e4. doi: 10.1016/j.molcel.2021.01.003. Epub 2021 Feb 5.
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 G 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.
多巴胺系统包括五个多巴胺受体（D1R-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。在这里，我们报告了两种与抑制性 G 蛋白结合并与 D3R 选择性激动剂 PD128907 和普拉克索结合的人 D3R 的冷冻电镜结构，后者用于治疗帕金森病患者。这些结构揭示了激动剂结合模式与拮抗剂结合的 D3R 结构不同，以及配体诱导的受体激活的构象特征。突变和同源建模阐明了多巴胺受体之间配体特异性的决定因素和 G 蛋白偶联的机制。总的来说，我们的工作揭示了激动剂结合和配体诱导的受体激活的基础，并为设计针对多巴胺能系统治疗 CNS 疾病的特异性配体提供了结构模板。
