ICAM-1 Peptide Inhibitors of T-cell Adhesion bind to the allosteric site of LFA-1. An NMR Characterization

Authors

  • Tahl Zimmerman,

    1. NMR Group, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
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  • Julen Oyarzabal,

    1. Medicinal Chemistry Department, Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
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  • Eider San Sebastián,

    1. Kimika Fakultatea, Euskal Herriko Unibertsitatea and Donostia International Physics Center, P.K. 1072, 28080 Donostia, Spain
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  • Sumit Majumdar,

    1. Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave, Lawrence, KS 66047, USA
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  • Bimo A. Tejo,

    1. Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave, Lawrence, KS 66047, USA
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  • Teruna J. Siahaan,

    1. Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave, Lawrence, KS 66047, USA
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  • Francisco J. Blanco

    Corresponding author
    1. NMR Group, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
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*Francisco J. Blanco, fblanco@cnio.es

Abstract

We have used nuclear magnetic resonance to characterize the binding site of two intercellular adhesion molecule-1 derived cyclic peptides, cIBC and cIBR, to the I-domain of leukocyte function-associated antigen-1. These peptides inhibit the leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction known to play a key role in autoimmune diseases and cancer metastasis. Perturbation of the chemical shifts and intensities of the nuclear magnetic resonance signals corresponding to a number of residues of the I-domain of leukocyte function-associated antigen-1 show that both peptides bind to the I-domain allosteric site, the binding site of I-domain allosteric inhibitors such as lovastatin, and therefore the peptides probably also act as allosteric inhibitors of leukocyte function-associated antigen-1. Molecular models of the interaction of these two cyclic peptides with leukocyte function-associated antigen-1 I-domain show that the binding mode of the three molecules are analogous: the hydrophobic residues of the peptides remain buried and occupy the same positions as the apolar groups of lovastatin, while the peptides regions containing the most polar residues are flexible and primarily exposed to the solvent. These results suggest an allosteric mechanism for the inhibitory effect on T-cell adhesion displayed by both peptides, which exhibit potential as therapeutic agents.

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