期刊
JOURNAL OF IMMUNOLOGY
卷 176, 期 7, 页码 4208-4220出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.176.7.4208
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资金
- NIAID NIH HHS [R01 AI057493] Funding Source: Medline
- NIDDK NIH HHS [K01 DK068383] Funding Source: Medline
- NINDS NIH HHS [R01 NS044914] Funding Source: Medline
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.
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