The D1- and D2-dopamine receptors (D1R and D2R), which signal through G_s and G_i, 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-G_s and D2R-G_i 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.

D1 和 D2 多巴胺受体（D1R 和 D2R）分别通过 G _s和 G 发出信号，代表中枢神经系统中主要的刺激性和抑制性多巴胺受体。 D1R 和 D2R 也是帕金森病、精神分裂症和许多其他神经精神疾病的主要治疗靶点，深入了解它们的信号传导对于了解多巴胺能药物的治疗和副作用至关重要。在这里，我们报道了 D1R- _G和 D2R-G 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病药物阿朴吗啡和溴隐亭。这些结构与诱变研究一起揭示了多巴胺激动剂的保守结合模式、配体选择性背后的独特口袋拓扑、受体激活的构象变化以及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，也提供了针对多巴胺能系统的药物设计的多种结构模板。