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anchor residue-modified \"heteroclitic\" peptides have been used in many cancer vaccine trials and often induce greater immune responses than the wild-type peptide. The best-studied system to date is the decamer MART-1/Melan-A26-35 peptide, EAAGIGILTV, where the natural alanine at position 2 has been modified to leucine to improve human leukocyte antigen (HLA)-A*0201 anchoring. The resulting ELAGIGILTV peptide has been used in many studies. We recently showed that T cells primed with the ELAGIGILTV peptide can fail to recognize the natural tumor-expressed peptide efficiently, thereby providing a potential molecular reason for why clinical trials of this peptide have been unsuccessful. Here, we solved the structure of a TCR in complex with HLA-A*0201-EAAGIGILTV peptide and compared it with its heteroclitic counterpart , HLA-A*0201-ELAGIGILTV. The data demonstrate that a suboptimal anchor residue at position 2 enables the TCR to \"pull\" the peptide away from the MHC binding groove, facilitating extra contacts with both the peptide and MHC surface. These data explain how a TCR can distinguish between two epitopes that differ by only a single MHC anchor residue and demonstrate how weak MHC anchoring can enable an induced-fit interaction with the TCR. Our findings constitute a novel demonstration of the extreme sensitivity of the TCR to minor alterations in peptide conformation.","bibjson":{"author":[{"initials":"F","lastname":"Madura","name":"Madura F"},{"initials":"PJ","lastname":"Rizkallah","name":"Rizkallah PJ"},{"initials":"CJ","lastname":"Holland","name":"Holland CJ"},{"initials":"A","lastname":"Fuller","name":"Fuller A"},{"initials":"A","lastname":"Bulek","name":"Bulek A"},{"initials":"AJ","lastname":"Godkin","name":"Godkin AJ"},{"initials":"AJ","lastname":"Schauenburg","name":"Schauenburg AJ"},{"initials":"DK","lastname":"Cole","name":"Cole DK"},{"initials":"AK","lastname":"Sewell","name":"Sewell AK"}],"identifier":[{"id":"10.1002/eji.201445114","type":"doi"},{"id":"25471691","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"Eur. J. 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