The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol
Llinas del Torrent, Claudia (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública)
Raïch, Iu (Universitat de Barcelona)
Gonzalez, Angel (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública)
Casajuana-Martin, Nil (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública)
Lillo, Jaume (Universitat de Barcelona)
Rebassa, Joan Biel (Universitat de Barcelona)
Ferreiro-Vera, Carlos (Phytoplant Research (Córdoba))
Sánchez de Medina, Verónica (Phytoplant Research (Córdoba))
Franco, Rafael (Universitat de Barcelona)
Navarro Rubio, Gemma (Universitat de Barcelona)
Pardo Carrasco, Leonardo (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública)

Data:	2023
Resum:	(-)-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.
Ajuts:	Agencia Estatal de Investigación BES-2017-081872 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00304 Agencia Estatal de Investigación PDC2022-133171-I00 Agencia Estatal de Investigación ID2020-113430RB-I00 Agencia Estatal de Investigación D2021-126600OB-I00 Agencia Estatal de Investigación PID2022-140912OB-I00
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	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
Publicat a:	Journal of chemical information and modeling, Vol. 63 Núm. 18 (25 2023) , p. 5927-5935, ISSN 1549-960X

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

9 p, 4.8 MB

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