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T cell receptors (TCRs) interact with peptides bound to the polymorphic major histocompatibility complex class Ia (MHC-Ia) and class II (MHC-II) molecules as well as the essentially monomorphic MHC class Ib (MHC-Ib) molecules. Although there is a large amount of information on how TCRs engage with MHC-Ia and MHC-II, our understanding of TCR/MHC-Ib interactions is very limited. Infection with cytomegalovirus (CMV) can elicit a CD8<sup>+</sup> T cell response restricted by the human MHC-Ib molecule human leukocyte antigen (HLA)-E and specific for an epitope from UL40 (VMAPRTLIL), which is characterized by biased TRBV14 gene usage. Here we describe an HLA-E-restricted CD8<sup>+</sup> T cell able to recognize an allotypic variant of the UL40 peptide with a modification at position 8 (P8) of the peptide (VMAPRTLVL) that uses the TRBV9 gene segment. We report the structures of a TRBV9<sup>+</sup> TCR in complex with the HLA-E molecule presenting the two peptides. Our data revealed that the TRBV9<sup>+</sup> TCR adopts a different docking mode and molecular footprint atop HLA-E when compared with the TRBV14<sup>+</sup> TCR-HLA-E ternary complex. Additionally, despite their differing V gene segment usage and different docking mechanisms, mutational analyses showed that the TCRs shared a conserved energetic footprint on the HLA-E molecule, focused around the peptide-binding groove. Hence, we provide new insights into how monomorphic MHC molecules interact with T cells.","bibjson":{"author":[{"initials":"LC","lastname":"Sullivan","name":"Sullivan LC"},{"initials":"NG","lastname":"Walpole","name":"Walpole NG"},{"initials":"C","lastname":"Farenc","name":"Farenc C"},{"initials":"G","lastname":"Pietra","name":"Pietra G"},{"initials":"MJW","lastname":"Sum","name":"Sum MJW"},{"initials":"CS","lastname":"Clements","name":"Clements CS"},{"initials":"EJ","lastname":"Lee","name":"Lee EJ"},{"initials":"T","lastname":"Beddoe","name":"Beddoe T"},{"initials":"M","lastname":"Falco","name":"Falco M"},{"initials":"MC","lastname":"Mingari","name":"Mingari MC"},{"initials":"L","lastname":"Moretta","name":"Moretta L"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"AG","lastname":"Brooks","name":"Brooks AG"}],"identifier":[{"id":"10.1074/jbc.M117.807719","type":"doi"},{"id":"28972140","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. Biol. Chem.","name":""},"pages":[null],"title":"A conserved energetic footprint underpins recognition of Human Leukocyte Antigen-E by two distinct \ufffd\ufffd\ufffd\ufffd T cell receptors.","type":"article","url":"https://www.sciencedirect.com/science/article/abs/pii/S0021925820327630","volume":[null],"year":[2017]},"in_pmc":"N","in_pmce":"Y","open_access":"N"},"resolution":"3.10","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/5w1w"},"rcsb":{"url":"https://www.rcsb.org/structure/5w1w"},"stcrdab":{"url":"http://opig.stats.ox.ac.uk/webapps/stcrdab/StrViewer?pdb=5w1w"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":{"alpha":{"chains":["D"],"subgroup":"TRAV35"},"beta":{"chains":["E"],"subgroup":"TRBV9"},"mhc_type":"class_i","pdb_code":"5w1w"},"title":"HLA-E*01:01 presenting \"VMAPRTLVL\" to Alpha/Beta T cell receptor at 3.10&#8491; resolution","unique_chain_count":5}}