| Literature DB >> 32004460 |
Changrui Xing1, Youwen Zhuang2, Ting-Hai Xu3, Zhiwei Feng1, X Edward Zhou3, Maozi Chen4, Lei Wang5, Xing Meng6, Ying Xue7, Junmei Wang4, Heng Liu5, Terence Francis McGuire4, Gongpu Zhao6, Karsten Melcher3, Cheng Zhang8, H Eric Xu9, Xiang-Qun Xie10.
Abstract
Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 activation and signaling are poorly understood but critical for drug design. Here we report the cryo-EM structure of the human CB2-Gi signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and Gi coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system.Entities:
Keywords: 3D Structure of Cannabinoid Receptor CB2; Activation Mechanisms of CB2 and CB1; Agonist-bound CB2- Gi Signaling Complex; CB2 Agonist; CB2 Coupling Specificity for Gi; CB2 Drug Discovery; CB2 Inverse Agonist; Cryo-EM structure; Gi Coupling Versatility; Residual Energy Contribution
Mesh：
Substances：
Year: 2020 PMID： 32004460 PMCID： PMC8247115 DOI： 10.1016/j.cell.2020.01.007
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582