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

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4378-4389
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number8
DOIs
Publication statusPublished - 15 Apr 2008

Keywords

  • Activation mechanism
  • Cannabinoid receptor
  • CB1
  • Comparative modeling
  • Conformational changes
  • Docking
  • GPCR
  • Ligand binding
  • Molecular dynamics
  • TMH

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