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leukocyte antigen (HLA)-I molecules can present long peptides, yet the mechanisms by which T-cell receptors (TCRs) recognize featured pHLA-I landscapes are unclear. We compared the binding modes of three distinct human TCRs, CA5, SB27, and SB47, complexed with a \"super-bulged\" viral peptide (LPEPLPQGQLTAY) restricted by HLA-B*35:08. The CA5 and SB27 TCRs engaged HLA-B*35:08(LPEP) similarly, straddling the central region of the peptide but making limited contacts with HLA-B*35:08. Remarkably, the CA5 TCR did not contact the \u03b11-helix of HLA-B*35:08. Differences in the CDR3\u03b2 loop between the CA5 and SB27 TCRs caused altered fine specificities. Surprisingly, the SB47 TCR engaged HLA-B*35:08(LPEP) using a completely distinct binding mechanism, namely \"bypassing\" the bulged peptide and making extensive contacts with the extreme N-terminal end of HLA-B*35:08. This docking footprint included HLA-I residues not observed previously as TCR contact sites. The three TCRs exhibited differing patterns of alloreactivity toward closely related or distinct HLA-I allotypes. Thus, the human T-cell repertoire comprises a range of TCRs that can interact with \"bulged\" pHLA-I epitopes using unpredictable strategies, including the adoption of atypical footprints on the MHC-I.","bibjson":{"author":[{"initials":"YC","lastname":"Liu","name":"Liu YC"},{"initials":"JJ","lastname":"Miles","name":"Miles JJ"},{"initials":"MA","lastname":"Neller","name":"Neller MA"},{"initials":"E","lastname":"Gostick","name":"Gostick E"},{"initials":"DA","lastname":"Price","name":"Price DA"},{"initials":"AW","lastname":"Purcell","name":"Purcell AW"},{"initials":"J","lastname":"McCluskey","name":"McCluskey J"},{"initials":"SR","lastname":"Burrows","name":"Burrows SR"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"S","lastname":"Gras","name":"Gras S"}],"identifier":[{"id":"10.1074/jbc.M112.447185","type":"doi"},{"id":"23569211","type":"pubmed"}],"issue":["22"],"journal":{"iso_abbreviation":"J. Biol. Chem.","name":""},"pages":["15442-54"],"title":"Highly divergent T-cell receptor binding modes underlie specific recognition of a bulged viral peptide bound to a human leukocyte antigen class I molecule.","type":"article","url":"https://www.sciencedirect.com/science/article/abs/pii/S0021925820459368","volume":["288"],"year":[2013]},"in_pmc":"Y","in_pmce":"Y","open_access":"Y"},"resolution":"2.80","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/4jry"},"rcsb":{"url":"https://www.rcsb.org/structure/4jry"},"stcrdab":{"url":"http://opig.stats.ox.ac.uk/webapps/stcrdab/StrViewer?pdb=4jry"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":{"alpha":{"chains":["D"],"subgroup":"TRAV39"},"beta":{"chains":["E"],"subgroup":"TRBV5"},"mhc_type":"class_i","pdb_code":"4jry"},"title":"HLA-B*35:08 presenting \"LPEPLPQGQLTAY\" to Alpha/Beta T cell receptor at 2.80&#8491; resolution","unique_chain_count":5}}
