title: Dynamic control of allosteric antagonism of leukocyte function antigen-1 and intercellular adhesion molecule-1 interaction.
abstract: 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 alpha7 helix, which may lead to the open form of the I-domain. The presence of an allosteric antagonist greatly reduces this motion of the alpha7 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.
authors.affiliation: Department of Molecular Systems, Merck Research Laboratories, Rahway, New Jersey 07065, USA. Kiyean_Nam@merck.com
authors.forename: Kiyean
authors.initials: K
authors.lastname: Nam
authors.forename: Vladimir
authors.initials: V
authors.lastname: Maiorov
authors.forename: Bradley
authors.initials: B
authors.lastname: Feuston
authors.forename: Simon
authors.initials: S
authors.lastname: Kearsley
mesh_terms: D000495:Allosteric Site; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1