Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures
| Autor: | Othman Benchama, Yiran Wu, Edward L. Stahl, Xiaoting Li, Qianqian Sun, Christos Iliopoulos-Tsoutsouvas, Shuguang Yuan, Xiyong Song, Suwen Zhao, Yuxia Wang, Nikolai Zvonok, Laura M. Bohn, Lijie Wu, Ling Shen, Christina A. Johnston, Travis W. Grim, Zhi-Jie Liu, Tian Hua, Shan Jiang, Meng Wu, Spyros P. Nikas, Alexandros Makriyannis, Feng Song |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Agonist
0303 health sciences Cannabinoid receptor medicine.drug_class Allosteric regulation Endogeny Biology Endocannabinoid system General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Docking (molecular) Neuropathic pain medicine lipids (amino acids peptides and proteins) Neuroscience 030217 neurology & neurosurgery 030304 developmental biology G protein-coupled receptor |
| Zdroj: | Cell. 180:655-665.e18 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2020.01.008 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|