Cell. 2018 Dec 21. pii: S0092-8674(18)31625-8. doi: 10.1016/j.cell.2018.12.011.
[Epub ahead of print]
Li X1, Hua T2, Vemuri K3, Ho JH4, Wu Y2, Wu L2, Popov P5, Benchama O3, Zvonok N3, Locke K4, Qu L2, Han GW6, Iyer MR7, Cinar R7, Coffey NJ7, Wang J1, Wu M8, Katritch V5, Zhao S9, Kunos G7, Bohn LM4, Makriyannis A3, Stevens RC10, Liu ZJ11.
Abstract
The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257’s unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.
Copyright © 2018 Elsevier Inc. All rights reserved.
KEYWORDS:
G-protein coupled receptor; cannabinoid receptor CB2; crystal structure; ligand design; subtype selectivity
- PMID: 30639103
- DOI: 10.1016/j.cell.2018.12.011
