The volatile anesthetic isoflurane perturbs conformational activation of integrin LFA-1 by binding to the allosteric regulatory cavity.
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.
Yuki
Koichi
K
Department of Anaesthesia, Harvard Medical School, 200 Longwood Ave., Rm 253, Boston, MA 02115, USA.
Astrof
Nathan S
NS
Bracken
Clay
C
Yoo
Ronnie
R
Silkworth
Whitney
W
Soriano
Sulpicio G
SG
Shimaoka
Motomu
M
D000495:Allosteric Site / Q000187:drug effects*; D018685:Anesthetics, Inhalation / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007530:Isoflurane / Q000737:chemistry* / Q000494:pharmacology*; D019169:Jurkat Cells; D020014:K562 Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry* / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D018685:Anesthetics, Inhalation; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D018799:Intercellular Adhesion Molecule-1; D007530:Isoflurane