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of peptides by class I or class II major histocompatibility complex (MHC) molecules is required for the initiation and propagation of a T cell-mediated immune response. Peptides from the Wilms Tumor 1 transcription factor (WT1), upregulated in many hematopoetic and solid tumors, can be recognized by T cells and numerous efforts are underway to engineer WT1-based cancer vaccines. Here we determined the structures of the class I MHC molecule HLA-A*0201 bound to the native 126-134 epitope of the WT1 peptide and a recently described variant (R1Y) with improved MHC binding. The R1Y variant, a potential vaccine candidate, alters the positions of MHC charged side chains near the peptide N-terminus and significantly reduces the peptide/MHC electrostatic surface potential. These alterations indicate that the R1Y variant is an imperfect mimic of the native WT1 peptide, and suggest caution in its use as a therapeutic vaccine. Stability measurements revealed how the R1Y substitution enhances MHC binding affinity, and together with the structures suggest a strategy for engineering WT1 variants with improved MHC binding that retain the structural features of the native peptide/MHC complex.","bibjson":{"author":[{"initials":"OY","lastname":"Borbulevych","name":"Borbulevych OY"},{"initials":"P","lastname":"Do","name":"Do P"},{"initials":"BM","lastname":"Baker","name":"Baker BM"}],"identifier":[{"id":"10.1016/j.molimm.2010.06.005","type":"doi"},{"id":"20619457","type":"pubmed"}],"issue":["15"],"journal":{"iso_abbreviation":"Mol. 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