State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China.
iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, 201210, Shanghai, China.
Nat Commun. 2020 Feb 26;11(1):1074. doi: 10.1038/s41467-020-14884-y.
The D dopamine receptor (DRD2) is one of the most well-established therapeutic targets for neuropsychiatric and endocrine disorders. Most clinically approved and investigational drugs that target this receptor are known to be subfamily-selective for all three D-like receptors, rather than subtype-selective for only DRD2. Here, we report the crystal structure of DRD2 bound to the most commonly used antipsychotic drug, haloperidol. The structures suggest an extended binding pocket for DRD2 that distinguishes it from other D-like subtypes. A detailed analysis of the structures illuminates key structural determinants essential for DRD2 activation and subtype selectivity. A structure-based and mechanism-driven screening combined with a lead optimization approach yield DRD2 highly selective agonists, which could be used as chemical probes for studying the physiological and pathological functions of DRD2 as well as promising therapeutic leads devoid of promiscuity.
D 多巴胺受体（DRD2）是神经精神和内分泌疾病最成熟的治疗靶点之一。大多数针对该受体的临床批准和研究药物已知对所有三种 D 样受体具有亚家族选择性，而不是仅对 DRD2 具有亚型选择性。在这里，我们报告了与最常用的抗精神病药物氟哌啶醇结合的 DRD2 的晶体结构。这些结构表明 DRD2 具有扩展的结合口袋，使其与其他 D 样亚型区分开来。对结构的详细分析揭示了对 DRD2 激活和亚型选择性至关重要的关键结构决定因素。基于结构的和基于机制的筛选以及先导优化方法产生了 DRD2 高度选择性激动剂，它们可用作研究 DRD2 的生理和病理功能的化学探针，以及具有非混杂性的有前途的治疗先导物。
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