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ICAM‐1 Peptide Inhibitors of T‐cell Adhesion bind to the allosteric site of LFA‐1. An NMR Characterization
Author(s) -
Zimmerman Tahl,
Oyarzabal Julen,
Sebastián Eider San,
Majumdar Sumit,
Tejo Bimo A.,
Siahaan Teruna J.,
Blanco Francisco J.
Publication year - 2007
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2007.00566.x
Subject(s) - allosteric regulation , chemistry , peptide , intercellular adhesion molecule 1 , biophysics , cell adhesion , binding site , cell adhesion molecule , intracellular , biochemistry , stereochemistry , microbiology and biotechnology , receptor , biology , cell
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.