• Home
  • Search Results
  • Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex.

Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex.

Cell (2020-02-01)
Changrui Xing, Youwen Zhuang, Ting-Hai Xu, Zhiwei Feng, X Edward Zhou, Maozi Chen, Lei Wang, Xing Meng, Ying Xue, Junmei Wang, Heng Liu, Terence Francis McGuire, Gongpu Zhao, Karsten Melcher, Cheng Zhang, H Eric Xu, Xiang-Qun Xie
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Leupeptin, microbial, ≥90% (HPLC)
Sigma-Aldrich
Guanosine 5′-diphosphate sodium salt, Type I, ≥96% (HPLC)
Sigma-Aldrich
2,2-Dimethyl-1,3-propanediol, 99%
Millipore
ANTI-FLAG® M1 Agarose Affinity Gel
Sigma-Aldrich
Cholesteryl hemisuccinate
Sigma-Aldrich
Benzamidine, ≥95.0%
Sigma-Aldrich
Cholesteryl hemisuccinate tris salt, anionic detergent
Sigma-Aldrich
Adenosine 3′,5′-cyclic monophosphate tris salt, ≥97% (HPLC), powder
Sigma-Aldrich
Maltose solution, BioReagent, for molecular biology, ~20% in H2O