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CD8 T cell response to the HLA-A2-restricted epitope LLWNGPMAV (LLW) of the non-structural protein 4b of Yellow Fever Virus (YFV) is remarkably immunodominant, highly prevalent and powerful in YFV-vaccinated humans. Here we used a combinatorial peptide library screening in the context of an A2/LLW-specific CD8 T cell clone to identify a superagonist that features a methionine to isoleucine substitution at position 7. Based on in silico modeling, the functional enhancement of this LLW-7I mutation was associated with alterations in the structural dynamics of the peptide in the major histocompatibility complex (pMHC) binding with the T cell receptor (TCR). While the TCR off-rate of LLW-7I pMHC is comparable to the wild type peptide, the rigidity of the 7I peptide seems to confer less entropy loss upon TCR binding. This LLW-7I superagonist is an example of improved functionality in human CD8 T cells associated with optimized ligand rigidity for TCR binding and not with changes in TCR:pMHC off-rate kinetics.","bibjson":{"author":[{"initials":"A","lastname":"Bovay","name":"Bovay A"},{"initials":"V","lastname":"Zoete","name":"Zoete V"},{"initials":"PJ","lastname":"Rizkallah","name":"Rizkallah PJ"},{"initials":"K","lastname":"Beck","name":"Beck K"},{"initials":"P","lastname":"Delbreil","name":"Delbreil P"},{"initials":"DE","lastname":"Speiser","name":"Speiser DE"},{"initials":"DK","lastname":"Cole","name":"Cole DK"},{"initials":"SA","lastname":"Fuertes Marraco","name":"Fuertes Marraco SA"}],"identifier":[{"id":"10.1016/j.molimm.2020.06.025","type":"doi"},{"id":"32645549","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"Mol. 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