The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol
(-)-Δ-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 (CBR) and CB (CBR) receptors. Molecular dynamics simulations showed that the pentyl c...
| Autores: | , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:307259 |
| Acceso en línea: | https://ddd.uab.cat/record/307259 https://dx.doi.org/urn:doi:10.1021/acs.jcim.3c01054 |
| Access Level: | acceso abierto |
| Palabra clave: | Alkyl chain Binding modes Cannabinoid receptors Cannabinoids Carbon chains Dynamics simulation G protein coupled receptors Intracellular cavities Receptor activation Side-chains Cannabinoid Receptor Agonists Dronabinol Receptor, Cannabinoid, CB1 Receptor, Cannabinoid, CB2 Receptors, Cannabinoid |
| Sumario: | (-)-Δ-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 (CBR) and CB (CBR) receptors. Molecular dynamics simulations showed that the pentyl chain of THC could adopts an I-shape conformation, filling an intracellular cavity between Phe and Trp for initial agonist-induced receptor activation, in CBR but not in CBR. This cavity opens to the five-carbon chain of THC by the conformational change of the γ-branched, flexible, Leu side chain of CBR, which is not feasible by the β-branched, mode rigid, Val side chain of CBR. In agreement with our computational results, THC could not decrease the forskolin-induced cAMP levels in cells expressing mutant CBR receptor but could activate the mutant CBR receptor as efficiently as wild-type CBR. Additionally, JWH-133, a full CBR agonist, contains a branched dimethyl moiety in the ligand chain that bridges Phe and Val for receptor activation. In this case, the substitution of Val to Leu in CBR makes JWH-133 unable to activate CBR. 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. |
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