Computational modeling study of functional microdomains in cannabinoid receptor type 1
Gonzalez, Angel (Pontificia Universidad Católica de Chile)
Sepulveda Duran, Leonardo (Pontificia Universidad Católica de Chile)
Araya-Secchi, Raul (Pontificia Universidad Católica de Chile)
Gárate, José Antonio (Pontificia Universidad Católica de Chile)
Pessoa-Mahana, David (Pontificia Universidad Católica de Chile)
Lagos, Carlos F. (Pontificia Universidad Católica de Chile)
Perez-Acle, T. (Pontificia Universidad Católica de Chile)

Fecha:	2008
Resumen:	The seven transmembrane helices (TMH) G-protein-coupled receptors (GPCRs) constitute one of the largest superfamily of signaling proteins found in mammals. Some of its members, in which the cannabinoid (CB) receptors are included, stand out because their functional states can be modulated by a broad spectrum of effector molecules. The relative ligand promiscuity exhibited by these receptors could be related with particular attributes conferred by their molecular architecture and represents a motivating issue to be explored. In this regard, this study represents an effort to investigate the cannabinoid receptor type 1 (CB1) ligand recognition plasticity, using comparative modeling, molecular dynamics (MD) simulations and docking. Our results suggest that a cooperative set of subtle structural rearrangements within the TMHs provide to the CB1 protein the plasticity to reach alternate configurations. These changes include the relaxation of intramolecular constraints, the rotations, translations and kinks of the majority of TMHs and the reorganization of the ligand binding cavities.
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Lengua:	Anglès
Documento:	Article ; recerca ; Versió sotmesa a revisió
Materia:	Cannabinoid receptor ; CB1 ; GPCR ; Activation mechanism ; TMH ; Ligand binding ; Docking ; Conformational changes ; Comparative modeling ; Molecular dynamics
Publicado en:	Bioorganic & medicinal chemistry, Vol. 16, Núm. 8 (April 2008) , p. 4378-4389, ISSN 0968-0896

DOI: 10.1016/j.bmc.2008.02.070

Preprint 44 p, 845.3 KB

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