3cch
H-2Db complex with murine gp100
Structural highlights
FunctionHA11_MOUSE Involved in the presentation of foreign antigens to the immune system. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedImmunogenicity of tumor-associated antigens (TAA) is often weak because many TAA are autoantigens for which the T-cell repertoire is sculpted by tolerance mechanisms. Substitutions at main anchor positions to increase the complementarity between the peptide and the MHC class I (MHC-I) binding cleft constitute a common procedure to improve binding capacity and immunogenicity of TAA. However, such alterations are tailored for each MHC-I allele and may recruit different CTL specificities through conformational changes in the targeted peptides. Comparative analysis of substituted melanoma-differentiation antigen gp100 in complex with H-2D(b) revealed that combined introduction of glycine and proline residues at the nonanchor positions 2 and 3, respectively, resulted in an agonistic altered peptide with dramatically enhanced binding affinity, stability, and immunogenicity of this TAA. Peptide vaccination using the p2Gp3P-altered peptide version of gp100 induced high frequencies of melanoma-specific CTL in the endogenous CD8+ repertoire. Crystal structure analysis of MHC/peptide complexes revealed that the conformation of the modified p2Gp3P-peptide was similar to the wild-type peptide, and indicated that this mimotope was stabilized through interactions between peptide residue p3P and the tyrosine residue Y159 that is conserved among most known MHC-I molecules throughout mammalian species. Our results may provide an alternative approach to enhance MHC stabilization capacity and immunogenicity of low-affinity peptides for induction of robust tumor-specific CTL. Design of agonistic altered peptides for the robust induction of CTL directed towards H-2Db in complex with the melanoma-associated epitope gp100.,van Stipdonk MJ, Badia-Martinez D, Sluijter M, Offringa R, van Hall T, Achour A Cancer Res. 2009 Oct 1;69(19):7784-92. Epub 2009 Sep 29. PMID:19789338[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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