PubMed: The Leu/Val<sup>6.51</sup> Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ<sup>9</sup>-Tetrahydrocannabinol

PubMed: The Leu/Val<sup>6.51</sup> Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ<sup>9</sup>-Tetrahydrocannabinol

J Chem Inf Model. 2023 Aug 29. doi: 10.1021/acs.jcim.3c01054. Online ahead of print.

ABSTRACT

(-)-Δ9trans-tetrahydrocannabinol (THC), which is the principal psychoactive constituent of Cannabis, mediates its action by binding to two members of the G-protein-coupled receptor (GPCR) family: the cannabinoid CB1 (CB1R) and CB2 (CB2R) receptors. Molecular dynamics simulations showed that the pentyl chain of THC could adopts an I-shape conformation, filling an intracellular cavity between Phe3.36 and Trp6.48 for initial agonist-induced receptor activation, in CB1R but not in CB2R. This cavity opens to the five-carbon chain of THC by the conformational change of the γ-branched, flexible, Leu6.51 side chain of CB1R, which is not feasible by the β-branched, mode rigid, Val6.51 side chain of CB2R. In agreement with our computational results, THC could not decrease the forskolin-induced cAMP levels in cells expressing mutant CB1RL6.51V receptor but could activate the mutant CB2RV6.51L receptor as efficiently as wild-type CB1R. Additionally, JWH-133, a full CB2R agonist, contains a branched dimethyl moiety in the ligand chain that bridges Phe3.36 and Val6.51 for receptor activation. In this case, the substitution of Val6.51 to Leu in CB2R makes JWH-133 unable to activate CB2RV6.51L. In conclusion, our combined computational and experimental results have shown that the amino acid at position 6.51 is a key additional player in the initial mechanism of activation of GPCRs that recognize signaling molecules derived from lipid species.

PMID:37644761 | DOI:10.1021/acs.jcim.3c01054

https://pubmed.ncbi.nlm.nih.gov/37644761/?utm_source=Chrome&utm_medium=rss&utm_campaign=pubmed-2&utm_content=1NqsX9BbHlDygQ8TcgAlJilHgPpiuKQtyIr–a3-xbLzPoB9xM&fc=20220928170152&ff=20230830190609&v=2.17.9.post6+86293ac August 30, 2023 10:00 am