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The volatile anesthetic isoflurane perturbs conformational activation of integrin LFA-1 by binding to the allosteric regulatory cavity

Koichi Yuki^*,,, Nathan S. Astrof^,,||, Clay Bracken^¶, Ronnie Yoo, Whitney Silkworth, Sulpicio G. Soriano^*, and Motomu Shimaoka^*,,1

^* Department of Anaesthesia,

Department of Pathology, and

Immune Disease Institute, Harvard Medical School, Boston, Massachusetts, USA;

Department of Anesthesiology, Perioperative and Pain Medicine, Children’s Hospital Boston, Boston, Massachusetts, USA;

^|| Cornell Medical School, New York, New York, USA; and

^¶ Department of Biochemistry, Weill Medical College, Cornell University, New York, New York, USA

¹Correspondence: Immune Disease Institute, Harvard Medical School, 200 Longwood Ave., Rm 253, Boston, MA 02115, USA. E-mail: shimaoka{at}idi.harvard.edu

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, K., Astrof, N. S., Bracken, C., Yoo, R., Silkworth, W., Soriano, S. G., Shimaoka, M. The volatile anesthetic isoflurane perturbs conformational activation of integrin LFA-1 by binding to the allosteric regulatory cavity.

Key Words: NMR • structure • small-molecule antagonist • leukocyte • cell adhesion