The volatile anesthetic isoflurane perturbs conformational activation of integrin LFA-1 by binding to the allosteric regulatory cavity. Academic Article uri icon

Overview

MeSH

  • Humans
  • Intercellular Adhesion Molecule-1
  • Jurkat Cells
  • K562 Cells
  • Macrophage-1 Antigen
  • Models, Biological
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Conformation
  • Up-Regulation

MeSH Major

  • Allosteric Site
  • Anesthetics, Inhalation
  • Isoflurane
  • Lymphocyte Function-Associated Antigen-1

abstract

  • The molecular and structural basis of anesthetic interactions with conformations and functionalities of cell surface receptors remains to be elucidated. We have demonstrated that the widely used volatile anesthetic isoflurane blocks the activation-dependent conformational conversion of integrin lymphocyte function associated antigen-1 (LFA-1), the major leukocyte cell adhesion molecule, to a high-affinity configuration. Perturbation of LFA-1 activation by isoflurane at clinically relevant concentrations leads to the inhibition of T-cell interactions with target cells as well as ligand-triggered intracellular signaling. Nuclear magnetic resonance spectroscopy reveals that isoflurane binds within a cavity in the LFA-1 ligand-binding domain, which is a previously identified drug-binding site for allosteric small-molecule antagonists that stabilize LFA-1 in a low-affinity conformation. These results provide a potential mechanism for the immunomodulatory properties of isoflurane.

publication date

  • December 2008

has subject area

  • Allosteric Site
  • Anesthetics, Inhalation
  • Humans
  • Intercellular Adhesion Molecule-1
  • Isoflurane
  • Jurkat Cells
  • K562 Cells
  • Lymphocyte Function-Associated Antigen-1
  • Macrophage-1 Antigen
  • Models, Biological
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Conformation
  • Up-Regulation

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2614612

Digital Object Identifier (DOI)

  • 10.1096/fj.08-113324

PubMed ID

  • 18708587

Additional Document Info

start page

  • 4109

end page

  • 4116

volume

  • 22

number

  • 12