Dynamic control of allosteric antagonism of leukocyte function antigen-1 and intercellular adhesion molecule-1 interaction |
| |
Authors: | Nam Kiyean Maiorov Vladimir Feuston Bradley Kearsley Simon |
| |
Affiliation: | Department of Molecular Systems, Merck Research Laboratories, Rahway, New Jersey 07065, USA. Kiyean_Nam@merck.com |
| |
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. |
| |
Keywords: | NMA (normal mode analysis) MD (molecular dynamics) MM‐PB(GB)SA (molecular mechanics Poisson‐Boltzmann [generalized Born] surface area) |
本文献已被 PubMed 等数据库收录! |