2016 Oct 20;167(3):750-762.e14. doi: 10.1016/j.cell.2016.10.004.
Hua T1, Vemuri K2, Pu M3, Qu L1, Han GW4, Wu Y5, Zhao S5, Shui W5, Li S5, Korde A2, Laprairie RB6, Stahl EL6, Ho JH6, Zvonok N2, Zhou H2, Kufareva I7, Wu B8, Zhao Q8, Hanson MA9, Bohn LM10, Makriyannis A11, Stevens RC12, Liu ZJ13.
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.
Copyright © 2016 Elsevier Inc. All rights reserved.
KEYWORDS:
AM6538; G protein-coupled receptor; THC; cannabinoid receptor CB1; cell signalling; crystal structure; marijuana; rimonabant; stabilizing antagonist
- PMID: 27768894
- DOI: 10.1016/j.cell.2016.10.004
- [PubMed – in process]
