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Crystal Structure of the Human Cannabinoid Receptor CB1. 2016
Tian Hua, and
Kiran Vemuri, and
Mengchen Pu, and
Lu Qu, and
Gye Won Han, and
Yiran Wu, and
Suwen Zhao, and
Wenqing Shui, and
Shanshan Li, and
Anisha Korde, and
Robert B Laprairie, and
Edward L Stahl, and
Jo-Hao Ho, and
Nikolai Zvonok, and
Han Zhou, and
Irina Kufareva, and
Beili Wu, and
Qiang Zhao, and
Michael A Hanson, and
Laura M Bohn, and
Alexandros Makriyannis, and
Raymond C Stevens, and
Zhi-Jie Liu
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
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.
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