上海科技大学刘志杰和华甜合作解析了大麻素受体-Gi复合物的结构并揭示了其激活和信号传导机制。该项研究成果在线发表在2020年1月30日出版的《细胞》上。

研究人员解析了Gi与合成大麻素CB2和CB1相结合复合物的冷冻电镜结构，以及CB2与激动剂结合的晶体结构。研究人员的结果揭示了多种激活和信号传导机制、为研发CB2选择性激动剂提供了结构基础以及意外发现胆固醇与CB1存在相互作用，提示其内源性变构调节作用；这些具有重要的科学和治疗意义。

据悉，人体内大麻素系统主要通过激活大麻素受体CB1和CB2来调节多种生理过程。它们高度相似的序列、激动剂的低选择性以及缺乏激活和G蛋白偶联相关知识阻碍了其治疗应用的发展。重要的是，由于缺少该受体的结构信息，这大大阻碍了以CB2为靶点的选择性激动剂药物的开发，该药物可用于治疗炎症和因CB1失活产生的神经性疼痛。

附：英文原文

Title: Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures

Author: Tian Hua, Xiaoting Li, Lijie Wu, Christos Iliopoulos-Tsoutsouvas, Yuxia Wang, Meng Wu, Ling Shen, Christina A. Johnston, Spyros P. Nikas, Feng Song, Xiyong Song, Shuguang Yuan, Qianqian Sun, Yiran Wu, Shan Jiang, Travis W. Grim, Othman Benchama, Edward L. Stahl, Nikolai Zvonok, Suwen Zhao, Laura M. Bohn, Alexandros Makriyannis, Zhi-Jie Liu

Issue&Volume: January 30, 2020

Abstract: Human endocannabinoid systems modulate multiple physiological processes mainly throughthe activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity,low agonist selectivity, and lack of activation and G protein-coupling knowledge havehindered the development of therapeutic applications. Importantly, missing structuralinformation has significantly held back the development of promising CB2-selectiveagonist drugs for treating inflammatory and neuropathic pain without the psychoactivityof CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-boundCB2 and CB1 in complex with Gi, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeuticbenefit, our results reveal a diverse activation and signaling mechanism, the structuralbasis of CB2-selective agonists design, and the unexpected interaction of cholesterolwith CB1, suggestive of its endogenous allosteric modulating role.

DOI: 10.1016/j.cell.2020.01.008

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30055-6