1. Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures.
- Author
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Hua, Tian, Li, Xiaoting, Wu, Lijie, Iliopoulos-Tsoutsouvas, Christos, Wang, Yuxia, Wu, Meng, Shen, Ling, Johnston, Christina A., Nikas, Spyros P., Song, Feng, Song, Xiyong, Yuan, Shuguang, Sun, Qianqian, Wu, Yiran, Jiang, Shan, Grim, Travis W., Benchama, Othman, Stahl, Edward L., Zvonok, Nikolai, and Zhao, Suwen
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CANNABINOID receptors , *G proteins , *G protein coupled receptors , *CRYSTAL structure - 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 G i , 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. • 3D structures of CB2-AM12033-G i , CB1-AM841-G i , and CB2-AM12033 are determined • Structural evidence of G protein selectivity by CB1 and CB2 is identified • MD simulations reveal the distinct binding behavior of HU308 in CB2 and CB1 • Cholesterol molecule as an endogenous allosteric modulator of CB1 is uncovered Structure and simulations of cannabinoid receptors CB2 and CB1 in their inactive, active-like, and activated signaling states reveal residue differences that may provide G protein selectivity, the distinct binding behavior of CB2 agonists in CB2 and CB1, as well as evidence for modulation of CB1 by cholesterol binding. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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