Crystal Structure of the Human Cannabinoid Receptor CB1

Tian Hua; Kiran Vemuri; Mengchen Pu; Lu Qu; Gye Won Han; Yiran Wu; Suwen Zhao; Wenqing Shui; Shanshan Li; Anisha Korde; Robert B Laprairie; Edward L Stahl; Jo-Hao Ho; Nikolai Zvonok; Han Zhou; Irina Kufareva; Beili Wu; Qiang Zhao; Michael A Hanson; Laura M Bohn; Alexandros Makriyannis; Raymond C Stevens; Zhi-Jie Liu

doi:10.1016/j.cell.2016.10.004

Crystal Structure of the Human Cannabinoid Receptor CB₁

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

Authors

Tian Hua¹, Kiran Vemuri², Mengchen Pu³, Lu Qu¹, Gye Won Han⁴, Yiran Wu⁵, Suwen Zhao⁵, Wenqing Shui⁵, Shanshan Li⁵, Anisha Korde², Robert B Laprairie⁶, Edward L Stahl⁶, Jo-Hao Ho⁶, Nikolai Zvonok², Han Zhou², Irina Kufareva⁷, Beili Wu⁸, Qiang Zhao⁸, Michael A Hanson⁹, Laura M Bohn¹⁰, Alexandros Makriyannis¹¹, Raymond C Stevens¹², Zhi-Jie Liu¹³

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Binding Sites
Cannabinoid Receptor Antagonists / chemistry*
Cannabinoids / pharmacology
Cannabis / chemistry
Crystallography, X-Ray
Dronabinol / pharmacology
Endocannabinoids / pharmacology
Humans
Ligands
Morpholines / chemical synthesis
Morpholines / chemistry*
Protein Binding
Protein Conformation, alpha-Helical
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
Receptor, Cannabinoid, CB1 / chemistry*

Substances

AM6545
Cannabinoid Receptor Antagonists
Cannabinoids
Endocannabinoids
Ligands
Morpholines
Pyrazoles
Receptor, Cannabinoid, CB1
Dronabinol

Abstract

Publication types

MeSH terms

Substances

Grants and funding