Computational modeling study of functional microdomains in cannabinoid receptor type 1

Angel Gonzalez, Leonardo Sepulveda Duran, Raul Araya-Secchi, Jose A. Garate, C. David Pessoa-Mahana, Carlos F. Lagos, Tomas Perez-Acle

Resultado de la investigación: Article

22 Citas (Scopus)

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.

Idioma originalEnglish
Páginas (desde-hasta)4378-4389
Número de páginas12
PublicaciónBioorganic and Medicinal Chemistry
Volumen16
N.º8
DOI
EstadoPublished - 15 abr 2008

Huella dactilar

Cannabinoid Receptors
Ligands
Plasticity
Cannabinoid Receptor CB1
Mammals
Molecular Dynamics Simulation
G-Protein-Coupled Receptors
Molecular dynamics
Proteins
Molecules
Computer simulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Citar esto

Gonzalez, A., Duran, L. S., Araya-Secchi, R., Garate, J. A., Pessoa-Mahana, C. D., Lagos, C. F., & Perez-Acle, T. (2008). Computational modeling study of functional microdomains in cannabinoid receptor type 1. Bioorganic and Medicinal Chemistry, 16(8), 4378-4389. https://doi.org/10.1016/j.bmc.2008.02.070
Gonzalez, Angel ; Duran, Leonardo Sepulveda ; Araya-Secchi, Raul ; Garate, Jose A. ; Pessoa-Mahana, C. David ; Lagos, Carlos F. ; Perez-Acle, Tomas. / Computational modeling study of functional microdomains in cannabinoid receptor type 1. En: Bioorganic and Medicinal Chemistry. 2008 ; Vol. 16, N.º 8. pp. 4378-4389.
@article{c3f7fc55c477495282dec2cc42914cc5,
title = "Computational modeling study of functional microdomains in cannabinoid receptor type 1",
abstract = "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.",
keywords = "Activation mechanism, Cannabinoid receptor, CB1, Comparative modeling, Conformational changes, Docking, GPCR, Ligand binding, Molecular dynamics, TMH",
author = "Angel Gonzalez and Duran, {Leonardo Sepulveda} and Raul Araya-Secchi and Garate, {Jose A.} and Pessoa-Mahana, {C. David} and Lagos, {Carlos F.} and Tomas Perez-Acle",
year = "2008",
month = "4",
day = "15",
doi = "10.1016/j.bmc.2008.02.070",
language = "English",
volume = "16",
pages = "4378--4389",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "8",

}

Gonzalez, A, Duran, LS, Araya-Secchi, R, Garate, JA, Pessoa-Mahana, CD, Lagos, CF & Perez-Acle, T 2008, 'Computational modeling study of functional microdomains in cannabinoid receptor type 1', Bioorganic and Medicinal Chemistry, vol. 16, n.º 8, pp. 4378-4389. https://doi.org/10.1016/j.bmc.2008.02.070

Computational modeling study of functional microdomains in cannabinoid receptor type 1. / Gonzalez, Angel; Duran, Leonardo Sepulveda; Araya-Secchi, Raul; Garate, Jose A.; Pessoa-Mahana, C. David; Lagos, Carlos F.; Perez-Acle, Tomas.

En: Bioorganic and Medicinal Chemistry, Vol. 16, N.º 8, 15.04.2008, p. 4378-4389.

Resultado de la investigación: Article

TY - JOUR

T1 - Computational modeling study of functional microdomains in cannabinoid receptor type 1

AU - Gonzalez, Angel

AU - Duran, Leonardo Sepulveda

AU - Araya-Secchi, Raul

AU - Garate, Jose A.

AU - Pessoa-Mahana, C. David

AU - Lagos, Carlos F.

AU - Perez-Acle, Tomas

PY - 2008/4/15

Y1 - 2008/4/15

N2 - 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.

AB - 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.

KW - Activation mechanism

KW - Cannabinoid receptor

KW - CB1

KW - Comparative modeling

KW - Conformational changes

KW - Docking

KW - GPCR

KW - Ligand binding

KW - Molecular dynamics

KW - TMH

UR - http://www.scopus.com/inward/record.url?scp=42349096001&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2008.02.070

DO - 10.1016/j.bmc.2008.02.070

M3 - Article

C2 - 18342519

AN - SCOPUS:42349096001

VL - 16

SP - 4378

EP - 4389

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 8

ER -

Gonzalez A, Duran LS, Araya-Secchi R, Garate JA, Pessoa-Mahana CD, Lagos CF y otros. Computational modeling study of functional microdomains in cannabinoid receptor type 1. Bioorganic and Medicinal Chemistry. 2008 abr 15;16(8):4378-4389. https://doi.org/10.1016/j.bmc.2008.02.070