Download MendeleySmall molecules that enhance the catalytic efficiency of HLA-DM.
Nicholson, M.J., Moradi, B., Seth, N.P., Xing, X., Cuny, G.D., Stein, R.L., Wucherpfennig, K.W.(2006) J Immunol 176: 4208-4220
- PubMed: 16547258
- DOI: https://doi.org/10.4049/jimmunol.176.7.4208
- Primary Citation of Related Structures:
2BC4 - PubMed Abstract:
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.
Organizational Affiliation:
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
