| Literature DB >> 27768894 |
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.
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.Entities:
Keywords: AM6538; G protein-coupled receptor; THC; cannabinoid receptor CB1; cell signalling; crystal structure; marijuana; rimonabant; stabilizing antagonist
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Year: 2016 PMID： 27768894 PMCID： PMC5322940 DOI： 10.1016/j.cell.2016.10.004
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582