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the major histocompatibility complex class I (MHC-I) molecules typically bind short peptide (p) fragments (8-10 amino acids in length), longer, \"bulged\" peptides are often be presented by MHC-I. Such bulged pMHC-I complexes represent challenges for T-cell receptor (TCR) ligation, although the general principles underscoring the interaction between TCRs and bulged pMHC-I complexes are unclear. To address this, we have explored the energetic basis of how an immunodominant TCR (termed SB27) binds to a 13-amino acid viral peptide (LPEPLPQGQLTAY) complexed to human leukocyte antigen (HLA) B*3508. Using the crystal structure of the SB27 TCR-HLA B*3508(LPEP) complex as a guide, we undertook a comprehensive alanine-scanning mutagenesis approach at the TCR-pMHC-I interface and examined the effect of the mutations by biophysical (affinity measurements) and cellular approaches (tetramer staining). Although the structural footprint on HLA B*3508 was small, the energetic footprint was even smaller in that only two HLA B*3508 residues were critical for the TCR interaction. Instead, the energetic basis of this TCR-pMHC-I interaction was attributed to peptide-mediated interactions in which the complementarity determining region 3\u03b1 and germline-encoded complementarity determining region 1\u03b2 loops of the SB27 TCR played the principal role. Our findings highlight the peptide-centricity of TCR ligation toward a bulged pMHC-I complex.","bibjson":{"author":[{"initials":"YC","lastname":"Liu","name":"Liu YC"},{"initials":"Z","lastname":"Chen","name":"Chen Z"},{"initials":"SR","lastname":"Burrows","name":"Burrows SR"},{"initials":"AW","lastname":"Purcell","name":"Purcell AW"},{"initials":"J","lastname":"McCluskey","name":"McCluskey J"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"S","lastname":"Gras","name":"Gras S"}],"identifier":[{"id":"10.1074/jbc.M112.344689","type":"doi"},{"id":"22343629","type":"pubmed"}],"issue":["15"],"journal":{"iso_abbreviation":"J. Biol. 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