Dopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases such as schizophrenia, Parkinson’s disease, depression, attention deficit hyperactivity disorder, and nausea and vomiting. The actions of dopamine are mediated by a family of five G-protein-coupled receptors. The D2 dopamine receptor (DRD2) is the primary target for both typical and atypical antipsychotic drugs, and for drugs used to treat Parkinson’s disease. Unfortunately, many drugs that target DRD2 cause serious and potentially life-threatening side effects due to promiscuous activities against related receptors. Accordingly, a molecular understanding of the structure and function of DRD2 could provide a template for the design of safer and more effective medications. Here we report the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2–risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and highlights structural determinants that are essential for the actions of risperidone and related drugs at DRD2.

中文翻译：

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与非典型抗精神病药物利培酮结合的 D2 多巴胺受体的结构

多巴胺是一种神经递质，与奖赏、成瘾、协调运动控制、新陈代谢和荷尔蒙分泌等多种过程有关。相应地，多巴胺能系统失调与精神分裂症、帕金森病、抑郁症、注意力缺陷多动障碍以及恶心和呕吐等疾病有关。多巴胺的作用由五个 G 蛋白偶联受体家族介导。D2 多巴胺受体 (DRD2) 是典型和非典型抗精神病药物以及用于治疗帕金森病的药物的主要靶标。不幸的是，由于对相关受体的混杂活性，许多靶向 DRD2 的药物会导致严重且可能危及生命的副作用。因此，对 DRD2 结构和功能的分子理解可以为设计更安全、更有效的药物提供模板。在这里，我们报告了与广泛使用的非典型抗精神病药物利培酮复合的 DRD2 的晶体结构。DRD2-利培酮结构揭示了抗精神病药物与多巴胺受体结合的意外模式，并突出了对利培酮和相关药物在 DRD2 上的作用至关重要的结构决定因素。