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

Cell
2020
Tian Hua∙ Xiaoting ∙ Lijie Wu ∙ Christos Iliopoulos-Tsoutsouvas ∙ Yuxia Wang ∙ Meng Wu ∙ Ling Shen ∙ Christina A. Brust ∙ 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

Summary

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