Department of Pharmaceutical Sciences, Computational Chemical Genomics Screen Center, School of Pharmacy, and NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15261, USA; Drug Discovery Institute and Departments of Computational Biology and of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of the Chinese Academy of Sciences, Beijing 100049, China; Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Institute, Grand Rapids, MI 49503, USA.
Cell. 2020 Feb 20;180(4):645-654.e13. doi: 10.1016/j.cell.2020.01.007. Epub 2020 Jan 30.
Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 activation and signaling are poorly understood but critical for drug design. Here we report the cryo-EM structure of the human CB2-G signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and G coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system.
药物选择性地靶向 CB2 有望治疗神经退行性疾病、炎症和疼痛，同时避免由 CB1 介导的精神副作用。CB2 激活和信号转导的机制了解甚少，但对药物设计至关重要。在这里，我们报告了与激动剂 WIN 55,212-2 结合的人 CB2-G 信号复合物的冷冻电镜结构。该 3D 结构揭示了 WIN 55,212-2 的结合模式和区分 CB2 激动剂与拮抗剂的结构决定因素，这得到了一对合理设计的激动剂和拮抗剂的支持。进一步的结构分析和计算对接结果揭示了 CB2 和 CB1 在受体激活、配体识别和 G 偶联方面的差异。这些发现有望促进基于结构的合理药物发现，以靶向大麻素系统。
