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CD8(+) cytotoxic T lymphocytes can mediate tumor regression in melanoma through the specific recognition of HLA-restricted peptides. Because of the relatively weak affinity of most anti-cancer T-cell receptors (TCRs), there is growing emphasis on immunizing melanoma patients with altered peptide ligands in order to induce strong anti-tumor immunity capable of breaking tolerance toward these self-antigens. However, previous studies have shown that these immunogenic designer peptides are not always effective. The melanocyte differentiation protein, glycoprotein 100 (gp100), encodes a naturally processed epitope that is an attractive target for melanoma immunotherapies, in particular peptide-based vaccines. Previous studies have shown that substitutions at peptide residue Glu(3) have a broad negative impact on polyclonal T-cell responses. Here, we describe the first atomic structure of a natural cognate TCR in complex with this gp100 epitope and highlight the relatively high affinity of the interaction. Alanine scan mutagenesis performed across the gp100(280-288) peptide showed that Glu(3) was critically important for TCR binding. Unexpectedly, structural analysis demonstrated that the Glu(3) \u2192 Ala substitution resulted in a molecular switch that was transmitted to adjacent residues, abrogating TCR binding and T-cell recognition. These findings help to clarify the mechanism of T-cell recognition of gp100 during melanoma responses and could direct the development of altered peptides for vaccination.","bibjson":{"author":[{"initials":"V","lastname":"Bianchi","name":"Bianchi V"},{"initials":"A","lastname":"Bulek","name":"Bulek A"},{"initials":"A","lastname":"Fuller","name":"Fuller A"},{"initials":"A","lastname":"Lloyd","name":"Lloyd A"},{"initials":"M","lastname":"Attaf","name":"Attaf M"},{"initials":"PJ","lastname":"Rizkallah","name":"Rizkallah PJ"},{"initials":"G","lastname":"Dolton","name":"Dolton G"},{"initials":"AK","lastname":"Sewell","name":"Sewell AK"},{"initials":"DK","lastname":"Cole","name":"Cole DK"}],"identifier":[{"id":"10.1074/jbc.M115.707414","type":"doi"},{"id":"26917722","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. Biol. 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