{"display":true,"structure":{"allele":{"alpha":{"identifier":"ipd-imgt:HLA34767","locus":"hla-a","match_type":"histo:fuzzy","name":"HLA-A*01:01","slug":"hla_a_01_01","species_stem":"hla"},"beta":{}},"assemblies":{"1":{"assembly_name":"5brz_1","chains":["A","B","C","D","E"],"downloaded_at":"2022-11-09T14:27:16.392215"}},"assembly_count":null,"assigned_chains":{"beta2m":{"chains":["B"],"match_type":"histo:assign_chains","score":0.99,"sequence":"MIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM"},"class_i_alpha":{"chains":["A"],"match_type":"histo:assign_chains","score":0.89,"sequence":"GSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQKMEPRAPWIEQEGPEYWDQETRNMKAHSQTDRANLGTLRGYYNQSEDGSHTIQIMYGCDVGPDGRFLRGYRQDAYDGKDYIALNEDLRSWTAADMAAQITKRKWEAVHAAEQRRVYLEGRCVDGLRRYLENGKETLQRTDPPKTHMTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDGTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRWP"},"peptide":{"chains":["C"],"match_type":"histo:classify_peptide","sequence":"EVDPIGHLY"},"tcr_alpha":{"chains":["D"],"match_type":"stcrdab","sequence":"AQEVTQIPAALSVPEGENLVLNCSFTDSAIYNLQWFRQDPGKGLTSLLYVRPYQREQTSGRLNASLDKSSGRSTLYIAASQPGDSATYLCAVRPGGAGPFFVVFGKGTKLSVIPNIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKCVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIP","subgroup":"TRAV21"},"tcr_beta":{"chains":["E"],"match_type":"stcrdab","sequence":"AGVTQTPRYLIKTRGQQVTLSCSPISGHRSVSWYQQTPGQGLQFLFEYFSETQRNKGNFPGRFSGRQFSNSRSEMNVSTLELGDSALYLCASSFNMATGQYFGPGTRLTVTEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVCTDPQPLKEQPALNDSRYALSSRLRVSATFWQDPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRAD","subgroup":"TRBV5"}},"chronology":{"deposition_date":"2015-06-01","deposition_year":2015,"release_date":"2016-03-02","release_year":2016,"revision_date":"2016-03-02","revision_year":2016},"class":"class_i","classical":true,"complex_type":"class_i_with_peptide_and_alpha_beta_tcr","components":["class_i_alpha","beta2m","peptide","tcr_alpha","tcr_beta"],"experimental_method":"X-ray diffraction","facets":{},"ligands":[],"locus":"hla-a","manually_edited":{},"missing_residues":[],"page_title":"5BRZ | HLA-A*01:01 presenting \"EVDPIGHLY\" to Alpha/Beta T cell receptor","pdb_code":"5brz","pdb_title":"Mage-a3 reactive TCR in complex with mage-a3 in hla-a1","peptide":{"C":{"actual_length":9,"actual_sequence":"EVDPIGHLY","chain_id":"C","features":["correct_sequence_and_length"],"full_length":9,"full_sequence":"EVDPIGHLY"}},"peptide_length":9,"peptide_length_name":"nonamer","peptide_neighbours":{"1":{"neighbours":[{"position":170,"residue":"ARG"},{"position":171,"residue":"TYR"},{"position":62,"residue":"GLN"},{"position":164,"residue":"CYS"},{"position":159,"residue":"TYR"},{"position":163,"residue":"ARG"},{"position":59,"residue":"TYR"},{"position":7,"residue":"TYR"},{"position":63,"residue":"GLU"},{"position":167,"residue":"GLY"},{"position":5,"residue":"MET"}],"position":1,"residue":"GLU"},"2":{"neighbours":[{"position":7,"residue":"TYR"},{"position":63,"residue":"GLU"},{"position":66,"residue":"ASN"},{"position":67,"residue":"MET"},{"position":9,"residue":"PHE"},{"position":99,"residue":"TYR"},{"position":159,"residue":"TYR"},{"position":163,"residue":"ARG"}],"position":2,"residue":"VAL"},"3":{"neighbours":[{"position":99,"residue":"TYR"},{"position":159,"residue":"TYR"},{"position":163,"residue":"ARG"},{"position":66,"residue":"ASN"},{"position":114,"residue":"ARG"},{"position":155,"residue":"GLN"},{"position":156,"residue":"ARG"}],"position":3,"residue":"ASP"},"4":{"neighbours":[{"position":159,"residue":"TYR"},{"position":163,"residue":"ARG"},{"position":69,"residue":"ALA"},{"position":66,"residue":"ASN"}],"position":4,"residue":"PRO"},"5":{"neighbours":[{"position":114,"residue":"ARG"},{"position":155,"residue":"GLN"},{"position":156,"residue":"ARG"}],"position":5,"residue":"ILE"},"6":{"neighbours":[{"position":156,"residue":"ARG"},{"position":73,"residue":"THR"}],"position":6,"residue":"GLY"},"7":{"neighbours":[{"position":155,"residue":"GLN"},{"position":156,"residue":"ARG"},{"position":147,"residue":"TRP"},{"position":73,"residue":"THR"},{"position":77,"residue":"ASN"},{"position":150,"residue":"VAL"},{"position":152,"residue":"ALA"}],"position":7,"residue":"HIS"},"8":{"neighbours":[{"position":76,"residue":"ALA"},{"position":147,"residue":"TRP"},{"position":73,"residue":"THR"},{"position":77,"residue":"ASN"},{"position":146,"residue":"LYS"},{"position":143,"residue":"THR"}],"position":8,"residue":"LEU"},"9":{"neighbours":[{"position":123,"residue":"TYR"},{"position":142,"residue":"ILE"},{"position":146,"residue":"LYS"},{"position":143,"residue":"THR"},{"position":97,"residue":"ILE"},{"position":124,"residue":"ILE"},{"position":116,"residue":"ASP"},{"position":81,"residue":"LEU"},{"position":80,"residue":"THR"},{"position":84,"residue":"TYR"},{"position":147,"residue":"TRP"},{"position":95,"residue":"ILE"},{"position":77,"residue":"ASN"}],"position":9,"residue":"TYR"}},"peptide_sequence":"EVDPIGHLY","pockets":{"a":{"a159":{"number":159,"one_letter":"Y","three_letter":"TYR"},"a163":{"number":163,"one_letter":"R","three_letter":"ARG"},"a167":{"number":167,"one_letter":"G","three_letter":"GLY"},"a171":{"number":171,"one_letter":"Y","three_letter":"TYR"},"a5":{"number":5,"one_letter":"M","three_letter":"MET"},"a59":{"number":59,"one_letter":"Y","three_letter":"TYR"},"a63":{"number":63,"one_letter":"E","three_letter":"GLU"},"a66":{"number":66,"one_letter":"N","three_letter":"ASN"},"a7":{"number":7,"one_letter":"Y","three_letter":"TYR"}},"b":{"a24":{"number":24,"one_letter":"A","three_letter":"ALA"},"a34":{"number":34,"one_letter":"V","three_letter":"VAL"},"a45":{"number":45,"one_letter":"M","three_letter":"MET"},"a63":{"number":63,"one_letter":"E","three_letter":"GLU"},"a66":{"number":66,"one_letter":"N","three_letter":"ASN"},"a67":{"number":67,"one_letter":"M","three_letter":"MET"},"a7":{"number":7,"one_letter":"Y","three_letter":"TYR"},"a70":{"number":70,"one_letter":"H","three_letter":"HIS"},"a9":{"number":9,"one_letter":"F","three_letter":"PHE"},"a99":{"number":99,"one_letter":"Y","three_letter":"TYR"}},"c":{"a70":{"number":70,"one_letter":"H","three_letter":"HIS"},"a73":{"number":73,"one_letter":"T","three_letter":"THR"},"a74":{"number":74,"one_letter":"D","three_letter":"ASP"},"a9":{"number":9,"one_letter":"F","three_letter":"PHE"},"a97":{"number":97,"one_letter":"I","three_letter":"ILE"}},"d":{"a114":{"number":114,"one_letter":"R","three_letter":"ARG"},"a155":{"number":155,"one_letter":"Q","three_letter":"GLN"},"a156":{"number":156,"one_letter":"R","three_letter":"ARG"},"a159":{"number":159,"one_letter":"Y","three_letter":"TYR"},"a160":{"number":160,"one_letter":"L","three_letter":"LEU"},"a99":{"number":99,"one_letter":"Y","three_letter":"TYR"}},"e":{"a114":{"number":114,"one_letter":"R","three_letter":"ARG"},"a147":{"number":147,"one_letter":"W","three_letter":"TRP"},"a152":{"number":152,"one_letter":"A","three_letter":"ALA"},"a156":{"number":156,"one_letter":"R","three_letter":"ARG"},"a97":{"number":97,"one_letter":"I","three_letter":"ILE"}},"f":{"a116":{"number":116,"one_letter":"D","three_letter":"ASP"},"a123":{"number":123,"one_letter":"Y","three_letter":"TYR"},"a143":{"number":143,"one_letter":"T","three_letter":"THR"},"a146":{"number":146,"one_letter":"K","three_letter":"LYS"},"a147":{"number":147,"one_letter":"W","three_letter":"TRP"},"a77":{"number":77,"one_letter":"N","three_letter":"ASN"},"a80":{"number":80,"one_letter":"T","three_letter":"THR"},"a81":{"number":81,"one_letter":"L","three_letter":"LEU"},"a84":{"number":84,"one_letter":"Y","three_letter":"TYR"},"a95":{"number":95,"one_letter":"I","three_letter":"ILE"}}},"publication":{"abstract":"Natural T-cell responses generally lack the potency to eradicate cancer. Enhanced affinity T-cell receptors (TCRs) provide an ideal approach to target cancer cells, with emerging clinical data showing significant promise. Nevertheless, the risk of off target reactivity remains a key concern, as exemplified in a recent clinical report describing fatal cardiac toxicity, following administration of MAGE-A3 specific TCR-engineered T-cells, mediated through cross-reactivity with an unrelated epitope from the Titin protein presented on cardiac tissue. Here, we investigated the structural mechanism enabling TCR cross-recognition of MAGE-A3 and Titin, and applied the resulting data to rationally design mutants with improved antigen discrimination, providing a proof-of-concept strategy for altering the fine specificity of a TCR towards an intended target antigen. This study represents the first example of direct molecular mimicry leading to clinically relevant fatal toxicity, mediated by a modified enhanced affinity TCR designed for cancer immunotherapy. Furthermore, these data demonstrate that self-antigens that are expressed at high levels on healthy tissue should be treated with extreme caution when designing immuno-therapeutics.","bibjson":{"author":[{"initials":"MC","lastname":"Raman","name":"Raman MC"},{"initials":"PJ","lastname":"Rizkallah","name":"Rizkallah PJ"},{"initials":"R","lastname":"Simmons","name":"Simmons R"},{"initials":"Z","lastname":"Donnellan","name":"Donnellan Z"},{"initials":"J","lastname":"Dukes","name":"Dukes J"},{"initials":"G","lastname":"Bossi","name":"Bossi G"},{"initials":"GS","lastname":"Le Provost","name":"Le Provost GS"},{"initials":"P","lastname":"Todorov","name":"Todorov P"},{"initials":"E","lastname":"Baston","name":"Baston E"},{"initials":"E","lastname":"Hickman","name":"Hickman E"},{"initials":"T","lastname":"Mahon","name":"Mahon T"},{"initials":"N","lastname":"Hassan","name":"Hassan N"},{"initials":"A","lastname":"Vuidepot","name":"Vuidepot A"},{"initials":"M","lastname":"Sami","name":"Sami M"},{"initials":"DK","lastname":"Cole","name":"Cole DK"},{"initials":"BK","lastname":"Jakobsen","name":"Jakobsen BK"}],"identifier":[{"id":"10.1038/srep18851","type":"doi"},{"id":"26758806","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"Sci Rep","name":""},"pages":["18851"],"title":"Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy.","type":"article","url":"https://www.nature.com/articles/srep18851","volume":["6"],"year":[2016]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"2.62","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/5brz"},"rcsb":{"url":"https://www.rcsb.org/structure/5brz"},"stcrdab":{"url":"http://opig.stats.ox.ac.uk/webapps/stcrdab/StrViewer?pdb=5brz"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":{"alpha":{"chains":["D"],"subgroup":"TRAV21"},"beta":{"chains":["E"],"subgroup":"TRBV5"},"mhc_type":"class_i","pdb_code":"5brz"},"title":"HLA-A*01:01 presenting \"EVDPIGHLY\" to Alpha/Beta T cell receptor at 2.62Å resolution","unique_chain_count":5}}