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Cell. 2016 Oct 20;167(3):750-762.e14. doi: 10.1016/j.cell.2016.10.004.

Crystal Structure of the Human Cannabinoid Receptor CB1.

Author information

1
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
2
Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
3
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
4
Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
5
iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
6
Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
7
University of California, San Diego, La Jolla, CA 92093, USA.
8
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
9
GPCR Consortium, San Marcos, CA 92078, USA.
10
Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: lbohn@scripps.edu.
11
Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA. Electronic address: a.makriyannis@northeastern.edu.
12
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: stevens@shanghaitech.edu.cn.
13
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: liuzhj@shanghaitech.edu.cn.

Abstract

Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.

KEYWORDS:

AM6538; G protein-coupled receptor; THC; cannabinoid receptor CB1; cell signalling; crystal structure; marijuana; rimonabant; stabilizing antagonist

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PMID:
27768894
PMCID:
PMC5322940
DOI:
10.1016/j.cell.2016.10.004
[Indexed for MEDLINE]
Free PMC Article

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