Revealing the Mechanism of Agonist-Mediated Cannabinoid Receptor 1 (CB1) Activation and Phospholipid-Mediated Allosteric Modulation

Óscar Díaz, James A.R. Dalton, Jesús Giraldo

Research output: Contribution to journalArticleResearch

8 Citations (Scopus)

Abstract

© 2019 American Chemical Society. Cannabinoid receptor 1 (CB1) mediates the functional responses of Δ9-tetrahydrocannabinol. Although progress has been made in understanding cannabinoid binding and receptor activation, detailed knowledge of the dynamics involved in the activation mechanism of CB1 is lacking. Here, we use recently determined CB1 crystal structures to analyze its transition from inactive to active state by performing unbiased microsecond-length molecular dynamics (MD) simulations, totaling 32 μs, with and without bound potent cannabinoid agonist CP-55940. CB1 activation is characterized by an upward axial movement of transmembrane (TM) helix 3, inward movement of TM7, and outward movement of TM6. These conformational changes collectively allow Gi protein docking, although fully active states of the receptor occur only transiently during MD simulations. Additionally, positive allosteric modulation of CB1 by anionic phospholipids is found to increase action of the bound agonist. Specifically, this involves protein-lipid interactions at intracellular loop 3, TM6, and ionic lock residue Arg2143.50.
Original languageEnglish
Pages (from-to)5638-5654
JournalJournal of Medicinal Chemistry
Volume62
DOIs
Publication statusPublished - 13 Jun 2019

Fingerprint Dive into the research topics of 'Revealing the Mechanism of Agonist-Mediated Cannabinoid Receptor 1 (CB1) Activation and Phospholipid-Mediated Allosteric Modulation'. Together they form a unique fingerprint.

Cite this