Nicholson Melissa J, Moradi Babak, Seth Nilufer P, Xing Xuechao, Cuny Gregory D, Stein Ross L, Wucherpfennig Kai W
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
J Immunol. 2006 Apr 1;176(7):4208-20. doi: 10.4049/jimmunol.176.7.4208.
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 DMbeta1 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.
HLA-DM（DM）通过催化与II类主要组织相容性复合体（MHC）分子结合的肽段交换，在向CD4 T细胞呈递抗原（Ag）过程中发挥关键作用。已明确了DM与HLA-DR（DR）相互作用中涉及的大的侧面，但催化机制尚不清楚。在本研究中，我们描述了四种加速DM催化的肽段交换的小分子。机制研究表明，这些小分子显著提高了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：两种化合物仅在有DM存在时才有活性，其中一种的结合数据显示与DM有直接相互作用。其余两种化合物在无DM时具有部分活性，表明它们可能作用于DM与DR/肽的界面。DMβ1结构域中的一个疏水脊与肽段交换的催化有关，因为该区域的点突变使其中三种增强剂的活性大幅降低。
