Nam Kiyean, Maiorov Vladimir, Feuston Bradley, Kearsley Simon
Department of Molecular Systems, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Proteins. 2006 Aug 1;64(2):376-84. doi: 10.1002/prot.20999.
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.
白细胞功能相关抗原-1（LFA-1）在T细胞迁移中起关键作用，并且已被公认为免疫紊乱的治疗靶点。已经开发出几类小分子拮抗剂来阻断LFA-1与细胞间黏附分子-1（ICAM-1）的相互作用。最近的结构研究表明，拮抗剂与LFA-1的I结构域中的变构位点结合。然而，由于在I结构域-拮抗剂复合结构中未观察到明显的构象变化，这些小分子作为拮抗剂的作用方式尚不清楚。在此，我们进行了一项计算研究，以揭示这些变构拮抗剂如何影响I结构域的动力学。从LFA-1 I结构域结构计算出的最低频率振动模式显示，C末端α7螺旋存在大规模的“卷曲向下”运动，这可能导致I结构域的开放形式。变构拮抗剂的存在极大地减少了α7螺旋以及I结构域其他部分的这种运动。因此，我们的研究表明，变构拮抗剂通过消除导致I结构域开放构象的呼吸运动来发挥作用。
