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Cell. 2020 Feb 20;180(4):645-654.e13. doi: 10.1016/j.cell.2020.01.007. Epub 2020 Jan 30.

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

Author information

1
Department of Pharmaceutical Sciences, Computational Chemical Genomics Screen Center, School of Pharmacy, and NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15261, USA; Drug Discovery Institute and Departments of Computational Biology and of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
2
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of the Chinese Academy of Sciences, Beijing 100049, China; Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Institute, Grand Rapids, MI 49503, USA.
3
Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Institute, Grand Rapids, MI 49503, USA.
4
Department of Pharmaceutical Sciences, Computational Chemical Genomics Screen Center, School of Pharmacy, and NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15261, USA.
5
Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
6
David Van Andel Advanced Cryo-Electron Microscopy Suite, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
7
Department of Pharmaceutical Sciences, Computational Chemical Genomics Screen Center, School of Pharmacy, and NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
8
Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: chengzh@pitt.edu.
9
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: eric.xu@simm.ac.cn.
10
Department of Pharmaceutical Sciences, Computational Chemical Genomics Screen Center, School of Pharmacy, and NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15261, USA; Drug Discovery Institute and Departments of Computational Biology and of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: xix15@pitt.edu.

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.

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

PMID:
32004460
DOI:
10.1016/j.cell.2020.01.007

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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