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PDBsum entry 1tvh
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Immune system
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PDB id
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1tvh
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References listed in PDB file
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Key reference
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Title
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Increased immunogenicity of an anchor-Modified tumor-Associated antigen is due to the enhanced stability of the peptide/mhc complex: implications for vaccine design.
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Authors
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O.Y.Borbulevych,
T.K.Baxter,
Z.Yu,
N.P.Restifo,
B.M.Baker.
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Ref.
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J Immunol, 2005,
174,
4812-4820.
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PubMed id
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Abstract
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The use of "anchor-fixed" altered peptide ligands is of considerable interest in
the development of therapeutic vaccines for cancer and infectious diseases, but
the mechanism by which successful altered peptide ligands elicit enhanced
immunity is unclear. In this study, we have determined the crystallographic
structure of a major tumor rejection Ag, gp100(209-217), in complex with the
HLA-A*0201 (HLA-A2) molecule, as well as the structure of a modified version of
the peptide which substitutes methionine for threonine at position 2 (T2M;
gp100(209-2M)). The T2M-modified peptide, which is more immunogenic in vitro and
in vivo, binds HLA-A2 with a approximately 9-fold greater affinity and has a
approximately 7-fold slower dissociation rate at physiological temperature.
Within the limit of the crystallographic data, the T2M substitution does not
alter the structure of the peptide/HLA-A2 complex. Consistent with this finding,
in peripheral blood from 95 human subjects, we were unable to identify higher
frequencies of T cells specific for either the native or modified peptide. These
data strongly support the conclusion that the greater immunogenicity of the
gp100(209-2M) peptide is due to the enhanced stability of the peptide/MHC
complex, validating the anchor-fixing approach for generating therapeutic
vaccine candidates. Thermodynamic data suggest that the enhanced stability of
the T2M-modified peptide/HLA-A2 complex is attributable to the increased
hydrophobicity of the modified peptide, but the gain due to hydrophobicity is
offset considerably by the loss of a hydrogen bond made by the native peptide to
the HLA-A2 molecule. Our findings have broad implications for the optimization
of current vaccine-design strategies.
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