Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA.
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158-2280, USA.
Nature. 2018 Mar 8;555(7695):269-273. doi: 10.1038/nature25758. Epub 2018 Jan 24.
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.
多巴胺是一种神经递质，涉及多种过程，如奖励、成瘾、协调运动的控制、代谢和激素分泌。相应地，多巴胺能系统的失调与精神分裂症、帕金森病、抑郁症、注意缺陷多动障碍以及恶心和呕吐等疾病有关。多巴胺的作用由一组 5 种 G 蛋白偶联受体介导。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点。不幸的是，许多针对 DRD2 的药物由于对相关受体的混杂活性而导致严重且潜在危及生命的副作用。因此，对 DRD2 的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 DRD2 与广泛开处方的非典型抗精神病药利培酮复合物的晶体结构。DRD2-利培酮结构揭示了一种意想不到的抗精神病药物与多巴胺受体结合的模式，并突出了结构决定因素，这些决定因素对于利培酮和相关药物在 DRD2 上的作用至关重要。
