| Literature DB >> 32004463 |
Tian Hua1, Xiaoting Li2, Lijie Wu2, Christos Iliopoulos-Tsoutsouvas3, Yuxia Wang2, Meng Wu4, Ling Shen4, Christina A Brust5, Spyros P Nikas3, Feng Song6, Xiyong Song7, Shuguang Yuan8, Qianqian Sun2, Yiran Wu2, Shan Jiang3, Travis W Grim5, Othman Benchama3, Edward L Stahl5, Nikolai Zvonok3, Suwen Zhao4, Laura M Bohn5, Alexandros Makriyannis9, Zhi-Jie Liu10.
Abstract
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.Entities:
Keywords: CB2-Gi; G protein-coupled receptor; activation; allosteric modulation; cannabinoid receptors; cholesterol; cryo-EM structures; crystal structure; subtype selectivity
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Year: 2020 PMID： 32004463 PMCID： PMC7898353 DOI： 10.1016/j.cell.2020.01.008
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582