Small molecules that enhance the catalytic efficiency of HLA-DM
Small molecules that enhance the catalytic efficiency of HLA-DM
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DOI：
10.4049/jimmunol.176.7.4208
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发表时间：
2006-04-01
影响因子：
4.4
通讯作者：
Wucherpfennig, Kai W.
中科院分区：
文献类型：
--
作者：
Nicholson, Melissa J.;Moradi, Babak;Wucherpfennig, Kai W.
HLA-DM（DM）通过催化与MHC II类分子结合的肽的交换，在Ag呈递至CD 4 T细胞中起关键作用。已经定义了DM：HLA-DR（DR）相互作用中涉及的大的侧表面，但是催化机制尚不清楚。在这项研究中，我们描述了四个小分子，加速DM催化的肽交换。机理研究表明，这些小分子大大提高了DM的催化效率，表明它们使DM：DR/肽复合物的过渡态在能量上更有利。这些化合物分为两个功能类别：两种化合物仅在DM存在下有活性，一种化合物的结合数据显示与DM直接相互作用。其余两种化合物在不存在DM的情况下具有部分活性，表明它们可能作用于DM和DR/肽之间的界面。DM β 1结构域中的疏水脊与肽交换的催化有关，因为这些增强子中的三个的活性通过该区域中的点突变而显著降低。
HLA-DM (DM) plays a critical role in Ag presentation to CD4 T-cells by catalyzing the exchange of peptides bound to MHC class II molecules. Large lateral surfaces involved in the DM:HLA-DR (DR) interaction have been defined, but the mechanism of catalysis is not understood. In this study, we describe four small molecules that accelerate DM-catalyzed peptide exchange. Mechanistic studies demonstrate that these small molecules substantially enhance the catalytic efficiency of DM, indicating that they make the transition state of the DM:DR/peptide complex energetically more favorable. These compounds fall into two functional classes: two compounds are active only in the presence of DM, and binding data for one show a direct interaction with DM. The remaining two compounds have partial activity in the absence of DM, suggesting that they may act at the interface between DM and DR/peptide. A hydrophobic ridge in the DM beta 1 domain was implicated in the catalysis of peptide exchange because the activity of three of these enhancers was substantially reduced by point mutations in this area.