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

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

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


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. The 3D structure of the agonist-bound CB2-Gi signaling complex provides insight into the key residues involved in ligand recognition and the distinction of agonists and antagonists critical for facilitating rational design of drugs targeting the cannabinoid system.

Original languageEnglish (US)
Pages (from-to)645-654.e13
Issue number4
StatePublished - Feb 20 2020
Externally publishedYes


  • 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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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