The Leu/Val^6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ⁹-Tetrahydrocannabinol

Abstract

Metrics & MoreArticle RecommendationsABSTRACT: (−)-Δ 9 -trans-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 CB 1 (CB 1 R) and CB 2 (CB 2 R) receptors. Molecular dynamics simulations showed that the pentyl chain of THC could adopts an I-shape conformation, filling an intracellular cavity between Phe 3.36 and Trp 6.48 for initial agonist-induced receptor activation, in CB 1 R but not in CB 2 R. This cavity opens to the five-carbon chain of THC by the conformational change of the γ-branched, flexible, Leu 6.51 side chain of CB 1 R, which is not feasible by the βbranched, mode rigid, Val 6.51 side chain of CB 2 R. In agreement with our computational results, THC could not decrease the forskolin-induced cAMP levels in cells expressing mutant CB 1 R L6.51V receptor but could activate the mutant CB 2 R V6.51L receptor as efficiently as wild-type CB 1 R. Additionally, JWH-133, a full CB 2 R agonist, contains a branched dimethyl moiety in the ligand chain that bridges Phe 3.36 and Val 6.51 for receptor activation. In this case, the substitution of Val 6.51 to Leu in CB 2 R makes JWH-133 unable to activate CB 2 R V6.51L . 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.

Homodimerization of CB2cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling

“…Figure 4B shows heatmaps of the predicted interactions of the second chromenopyrazole pharmacophore of PM369 with amino acids of the membrane-facing pocket between TMs 1 and 7 of the inactive CB2R protomer. A chemical signature of cannabinoid agonists is branched dimethyl moieties that induce receptor activation through hydrophobic interactions with Phe117 3.36 in the g+ conformation and Val261 6.51 [58,59]. The pharmacophore group of homobivalent ligand PM369 contains these branched dimethyl moieties at the was not certified by peer review) is the author/funder.…”

“…In contrast, the structure reported by Wang et al [51] adopts a tilt angle of 46º comparable to the value observed in the complex with V2R (Figure 6D). In both structures the C-domain of β-arrestin is oriented towards the cell membrane, where the Cedge loop acts as a membrane anchor [59]; whereas Lys158 localized at the tip of the Ndomain of β-arrestin is facing the inactive protomer of the CB2R-CB2R homodimer (Figures 6E-6F). However, in the 8WRZ structure of Wang et al Lys158 points towards ICL3 of the inactive protomer (Figure 6F), whereas in the 8WU1 structure of Liao et al Lys158 points towards H8 and it is Arg162 that points towards ICL3 (Figure 6E).…”