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

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Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures.
Cell ( IF 45.5 ) Pub Date : 2020-01-30 , DOI: 10.1016/j.cell.2020.01.008
Tian Hua ₁ , Xiaoting Li ₁ , Lijie Wu ₁ , Christos Iliopoulos-Tsoutsouvas ₂ , Yuxia Wang ₁ , Meng Wu ₃ , Ling Shen ₃ , Christina A Brust ₄ , Spyros P Nikas ₂ , Feng Song ₅ , Xiyong Song ₆ , Shuguang Yuan ₇ , Qianqian Sun ₁ , Yiran Wu ₁ , Shan Jiang ₂ , Travis W Grim ₄ , Othman Benchama ₂ , Edward L Stahl ₄ , Nikolai Zvonok ₂ , Suwen Zhao ₃ , Laura M Bohn ₄ , Alexandros Makriyannis ₈ , Zhi-Jie Liu ₉

Affiliation

iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Departments of Molecular Medicine and Neuroscience, Scripps Research, Jupiter, FL 33458, USA.
School of Life Science, Dezhou University, Dezhou 253023, Shandong Province, China.
Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, Yunnan Province, China.
The Research Center for Computer-aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; Center for Drug Discovery and Departments of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, Yunnan Province, China.

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.

中文翻译：

大麻受体-Gi复合结构揭示了激活和信号传导机制。

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。它们的高序列相似性，低激动剂选择性以及缺乏激活和G蛋白偶联知识阻碍了治疗应用的发展。重要的是，缺失的结构信息已大大阻碍了有前途的CB2选择性激动剂药物的开发，该药物可用于治疗无CB1的精神性炎症和神经性疼痛。在这里，我们报告与大麻素复合的合成大麻素结合的CB2和CB1的低温电子显微镜结构，以及激动剂结合的CB2晶体结构。我们的研究结果揭示了多种激活和信号传导机制，CB2选择性激动剂设计的结构基础，

更新日期：2020-01-31

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