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
Cell October 20, 2016 DOI: 10.1016/j.cell.2016.10.004 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Structural biology study (crystallography with functional studies and molecular modeling) Peer reviewed |
|---|---|
| Intervention | AM6538 |
| Topics | Cannabis |
| Keywords | Am6538 G protein-coupled receptor Cannabinoid receptor cb1 Cell signalling Crystal structure Rimonabant Stabilizing antagonist |
| Key points | The 2.8 Å crystal structure of human CB1 bound to the antagonist AM6538 reveals key receptor features and the interactions underlying antagonist binding. Combined with functional studies and molecular modeling, the authors report that it provides insight into the binding modes of THC and synthetic cannabinoids, which they say could inform design of new CB1-targeting pharmaceuticals. |
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.
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