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Cell. 2020 Feb 20;180(4):655-665.e18. doi: 10.1016/j.cell.2020.01.008. Epub 2020 Jan 30.

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

Author information

1
iHuman Institute, ShanghaiTech University, Shanghai 201210, China. Electronic address: huatian@shanghaitech.edu.cn.
2
iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
3
Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
4
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
5
Departments of Molecular Medicine and Neuroscience, Scripps Research, Jupiter, FL 33458, USA.
6
School of Life Science, Dezhou University, Dezhou 253023, Shandong Province, China.
7
Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, Yunnan Province, China.
8
The Research Center for Computer-aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
9
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.
10
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. Electronic address: liuzhj@shanghaitech.edu.cn.

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.

KEYWORDS:

CB2-Gi; G protein-coupled receptor; activation; allosteric modulation; cannabinoid receptors; cholesterol; cryo-EM structures; crystal structure; subtype selectivity

PMID:
32004463
DOI:
10.1016/j.cell.2020.01.008

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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