Crystal Structure of the Human Cannabinoid Receptor CB2

Xiaoting Li, Tian Hua, Kiran Vemuri, Jo-Hao Ho, Yiran Wu, Lijie Wu, Petr Popov, Othman Benchama, Nikolai Zvonok, K'ara Locke, Lu Qu, Gye Won Han, Malliga R Iyer, Resat Cinar, Nathan J Coffey, Jingjing Wang, Meng Wu, Vsevolod Katritch, Suwen Zhao, George Kunos, Laura M Bohn, Alexandros Makriyannis, Raymond C Stevens, Zhi-Jie Liu
Cell 2018 December 21
The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257's unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.


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lin gugu

人类大麻素受体CB2的晶体结构。大麻素受体CB2主要在免疫系统中表达,选择性调节CB2而不受CB1的精神活性影响,在炎症、纤维化和神经退行性疾病中具有治疗潜力。在此,我们报告了人类CB2的晶体结构与合理设计的拮抗剂AM10257在2.8 a分辨率下的复合物。与CB1相比,CB2-AM10257结构显示出明显不同的结合姿态。然而,拮抗结合CB2的细胞外部分与拮抗结合CB1具有高度的构象相似性,这导致AM10257出人意料地发现了CB2拮抗与CB1激动作用相反的功能谱。进一步利用诱变研究和分子对接进行结构分析,揭示了它们对CB2和CB1的功能和选择性的分子基础。对我们设计的拮抗剂和激动剂对的进一步分析为CB2的激活机制提供了重要的见解。本研究结果将有助于合理设计药物,以精确调控内源性大麻素系统。


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