Premium
Dynamic control of allosteric antagonism of leukocyte function antigen‐1 and intercellular adhesion molecule‐1 interaction
Author(s) -
Nam Kiyean,
Maiorov Vladimir,
Feuston Bradley,
Kearsley Simon
Publication year - 2006
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20999
Subject(s) - allosteric regulation , biophysics , chemistry , allosteric enzyme , intercellular adhesion molecule 1 , small molecule , function (biology) , cell adhesion molecule , intracellular , microbiology and biotechnology , receptor , biology , biochemistry
Leukocyte function associated antigen‐1 (LFA‐1) plays a critical role in T cell migration and has been recognized as a therapeutic target for immune disorders. Several classes of small molecule antagonists have been developed to block LFA‐1 interaction with intercellular adhesion molecule‐1 (ICAM‐1). Recent structural studies show that the antagonists bind to an allosteric site in the I‐domain of LFA‐1. However, it is not yet clear how these small molecules work as antagonists since no significant conformational change is observed in the I‐domain–antagonist complex structures. Here we present a computational study suggesting how these allosteric antagonists affect the dynamics of the I‐domain. The lowest frequency vibrational mode calculated from an LFA‐1 I‐domain structure shows large scale “coil‐down” motion of the C‐terminal α7 helix, which may lead to the open form of the I‐domain. The presence of an allosteric antagonist greatly reduces this motion of the α7 helix as well as other parts of the I‐domain. Thus, our study suggests that allosteric antagonists work by eliminating breathing motion that leads to the open conformation of the I‐domain. Proteins 2006. © 2006 Wiley‐Liss, Inc.