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PDBsum entry 2bc4
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Immune system
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PDB id
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2bc4
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References listed in PDB file
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Key reference
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Title
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Small molecules that enhance the catalytic efficiency of hla-Dm.
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Authors
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M.J.Nicholson,
B.Moradi,
N.P.Seth,
X.Xing,
G.D.Cuny,
R.L.Stein,
K.W.Wucherpfennig.
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Ref.
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J Immunol, 2006,
176,
4208-4220.
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PubMed id
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Abstract
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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.
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