{"display":true,"structure":{"allele":{"alpha":{"identifier":"ipd-imgt:HLA35228","locus":"hla-b","match_type":"histo:exact","name":"HLA-B*15:01","slug":"hla_b_15_01","species_stem":"hla"},"beta":{}},"assemblies":{"1":{"assembly_name":"5txs_1","chains":["A","B","C"],"downloaded_at":"2022-11-09T14:44:21.596444"}},"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":"MGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRFDSDAASPRMAPRAPWIEQEGPEYWDRETQISKTNTQTYRESLRNLRGYYNQSEAGSHTLQRMYGCDVGPDGRLLRGHDQSAYDGKDYIALNEDLSSWTAADTAAQITQRKWEAAREAEQWRAYLEGLCVEWLRRYLENGKETLQRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPAGDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRWEPSSQSGSLHHILDAQKMVWNHR"},"peptide":{"chains":["C"],"match_type":"histo:classify_peptide","sequence":"AQDIYRASY"}},"chronology":{"deposition_date":"2016-11-17","deposition_year":2016,"release_date":"2017-11-29","release_year":2017,"revision_date":"2018-03-21","revision_year":2018},"class":"class_i","classical":true,"complex_type":"class_i_with_peptide","components":["class_i_alpha","beta2m","peptide"],"experimental_method":"X-ray diffraction","facets":{},"ligands":[],"locus":"hla-b","manually_edited":{},"missing_residues":[],"page_title":"5TXS | HLA-B*15:01 binding \"AQDIYRASY\"","pdb_code":"5txs","pdb_title":"Crystal structure of an anaplastic lymphoma kinase-derived neuroblastoma tumor antigen bound to the human major histocompatibility complex Class I molecule hla-b*1501","peptide":{"C":{"actual_length":9,"actual_sequence":"AQDIYRASY","chain_id":"C","features":["correct_sequence_and_length"],"full_length":9,"full_sequence":"AQDIYRASY"}},"peptide_length":9,"peptide_length_name":"nonamer","peptide_neighbours":{"1":{"neighbours":[{"position":99,"residue":"TYR"},{"position":33,"residue":"PHE"},{"position":5,"residue":"MET"},{"position":159,"residue":"TYR"},{"position":59,"residue":"TYR"},{"position":163,"residue":"LEU"},{"position":62,"residue":"ARG"},{"position":63,"residue":"GLU"},{"position":164,"residue":"CYS"},{"position":7,"residue":"TYR"},{"position":167,"residue":"TRP"},{"position":171,"residue":"TYR"}],"position":1,"residue":"ALA"},"2":{"neighbours":[{"position":67,"residue":"SER"},{"position":159,"residue":"TYR"},{"position":62,"residue":"ARG"},{"position":34,"residue":"VAL"},{"position":7,"residue":"TYR"},{"position":9,"residue":"TYR"},{"position":24,"residue":"ALA"},{"position":22,"residue":"PHE"},{"position":63,"residue":"GLU"},{"position":70,"residue":"ASN"},{"position":99,"residue":"TYR"},{"position":66,"residue":"ILE"},{"position":45,"residue":"MET"}],"position":2,"residue":"GLN"},"3":{"neighbours":[{"position":62,"residue":"ARG"},{"position":156,"residue":"TRP"},{"position":7,"residue":"TYR"},{"position":159,"residue":"TYR"},{"position":9,"residue":"TYR"},{"position":70,"residue":"ASN"},{"position":99,"residue":"TYR"},{"position":66,"residue":"ILE"}],"position":3,"residue":"ASP"},"4":{"neighbours":[{"position":159,"residue":"TYR"},{"position":62,"residue":"ARG"},{"position":65,"residue":"GLN"},{"position":66,"residue":"ILE"}],"position":4,"residue":"ILE"},"5":{"neighbours":[{"position":76,"residue":"GLU"},{"position":73,"residue":"THR"},{"position":74,"residue":"TYR"},{"position":65,"residue":"GLN"},{"position":69,"residue":"THR"},{"position":77,"residue":"SER"},{"position":70,"residue":"ASN"},{"position":66,"residue":"ILE"}],"position":5,"residue":"TYR"},"6":{"neighbours":[{"position":159,"residue":"TYR"},{"position":152,"residue":"GLU"},{"position":155,"residue":"GLN"},{"position":156,"residue":"TRP"}],"position":6,"residue":"ARG"},"7":{"neighbours":[{"position":147,"residue":"TRP"},{"position":77,"residue":"SER"},{"position":152,"residue":"GLU"},{"position":146,"residue":"LYS"},{"position":150,"residue":"ALA"},{"position":97,"residue":"ARG"}],"position":7,"residue":"ALA"},"8":{"neighbours":[{"position":147,"residue":"TRP"},{"position":77,"residue":"SER"},{"position":146,"residue":"LYS"},{"position":73,"residue":"THR"},{"position":143,"residue":"THR"},{"position":76,"residue":"GLU"},{"position":80,"residue":"ASN"}],"position":8,"residue":"SER"},"9":{"neighbours":[{"position":81,"residue":"LEU"},{"position":147,"residue":"TRP"},{"position":123,"residue":"TYR"},{"position":77,"residue":"SER"},{"position":124,"residue":"ILE"},{"position":115,"residue":"GLN"},{"position":84,"residue":"TYR"},{"position":117,"residue":"ALA"},{"position":146,"residue":"LYS"},{"position":74,"residue":"TYR"},{"position":116,"residue":"SER"},{"position":96,"residue":"GLN"},{"position":143,"residue":"THR"},{"position":97,"residue":"ARG"},{"position":95,"residue":"LEU"},{"position":80,"residue":"ASN"}],"position":9,"residue":"TYR"}},"peptide_sequence":"AQDIYRASY","pockets":{"a":{"a159":{"number":159,"one_letter":"A","three_letter":"ALA"},"a163":{"number":163,"one_letter":"G","three_letter":"GLY"},"a167":{"number":167,"one_letter":"E","three_letter":"GLU"},"a171":{"number":171,"one_letter":"R","three_letter":"ARG"},"a5":{"number":5,"one_letter":"S","three_letter":"SER"},"a59":{"number":59,"one_letter":"E","three_letter":"GLU"},"a63":{"number":63,"one_letter":"R","three_letter":"ARG"},"a66":{"number":66,"one_letter":"Q","three_letter":"GLN"},"a7":{"number":7,"one_letter":"R","three_letter":"ARG"}},"b":{"a24":{"number":24,"one_letter":"I","three_letter":"ILE"},"a34":{"number":34,"one_letter":"F","three_letter":"PHE"},"a45":{"number":45,"one_letter":"R","three_letter":"ARG"},"a63":{"number":63,"one_letter":"R","three_letter":"ARG"},"a66":{"number":66,"one_letter":"Q","three_letter":"GLN"},"a67":{"number":67,"one_letter":"I","three_letter":"ILE"},"a7":{"number":7,"one_letter":"R","three_letter":"ARG"},"a70":{"number":70,"one_letter":"T","three_letter":"THR"},"a9":{"number":9,"one_letter":"F","three_letter":"PHE"},"a99":{"number":99,"one_letter":"M","three_letter":"MET"}},"c":{"a70":{"number":70,"one_letter":"T","three_letter":"THR"},"a73":{"number":73,"one_letter":"Q","three_letter":"GLN"},"a74":{"number":74,"one_letter":"T","three_letter":"THR"},"a9":{"number":9,"one_letter":"F","three_letter":"PHE"},"a97":{"number":97,"one_letter":"Q","three_letter":"GLN"}},"d":{"a114":{"number":114,"one_letter":"H","three_letter":"HIS"},"a155":{"number":155,"one_letter":"E","three_letter":"GLU"},"a156":{"number":156,"one_letter":"Q","three_letter":"GLN"},"a159":{"number":159,"one_letter":"A","three_letter":"ALA"},"a160":{"number":160,"one_letter":"Y","three_letter":"TYR"},"a99":{"number":99,"one_letter":"M","three_letter":"MET"}},"e":{"a114":{"number":114,"one_letter":"H","three_letter":"HIS"},"a147":{"number":147,"one_letter":"K","three_letter":"LYS"},"a152":{"number":152,"one_letter":"R","three_letter":"ARG"},"a156":{"number":156,"one_letter":"Q","three_letter":"GLN"},"a97":{"number":97,"one_letter":"Q","three_letter":"GLN"}},"f":{"a116":{"number":116,"one_letter":"Q","three_letter":"GLN"},"a123":{"number":123,"one_letter":"D","three_letter":"ASP"},"a143":{"number":143,"one_letter":"I","three_letter":"ILE"},"a146":{"number":146,"one_letter":"R","three_letter":"ARG"},"a147":{"number":147,"one_letter":"K","three_letter":"LYS"},"a77":{"number":77,"one_letter":"E","three_letter":"GLU"},"a80":{"number":80,"one_letter":"R","three_letter":"ARG"},"a81":{"number":81,"one_letter":"N","three_letter":"ASN"},"a84":{"number":84,"one_letter":"G","three_letter":"GLY"},"a95":{"number":95,"one_letter":"T","three_letter":"THR"}}},"publication":{"abstract":"The identification of recurrent human leukocyte antigen (HLA) neoepitopes driving T cell responses against tumors poses a significant bottleneck in the development of approaches for precision cancer therapeutics. Here, we employ a bioinformatics method, Prediction of T Cell Epitopes for Cancer Therapy, to analyze sequencing data from neuroblastoma patients and identify a recurrent anaplastic lymphoma kinase mutation (ALK R1275Q) that leads to two high affinity neoepitopes when expressed in complex with common HLA alleles. Analysis of the X-ray structures of the two peptides bound to HLA-B*15:01 reveals drastically different conformations with measurable changes in the stability of the protein complexes, while the self-epitope is excluded from binding due to steric hindrance in the MHC groove. To evaluate the range of HLA alleles that could display the ALK neoepitopes, we used structure-based Rosetta comparative modeling calculations, which accurately predict several additional high affinity interactions and compare our results with commonly used prediction tools. Subsequent determination of the X-ray structure of an HLA-A*01:01 bound neoepitope validates atomic features seen in our Rosetta models with respect to key residues relevant for MHC stability and T cell receptor recognition. Finally, MHC tetramer staining of peripheral blood mononuclear cells from HLA-matched donors shows that the two neoepitopes are recognized by CD8+ T cells. This work provides a rational approach toward high-throughput identification and further optimization of putative neoantigen/HLA targets with desired recognition features for cancer immunotherapy.","bibjson":{"author":[{"initials":"JS","lastname":"Toor","name":"Toor JS"},{"initials":"AA","lastname":"Rao","name":"Rao AA"},{"initials":"AC","lastname":"McShan","name":"McShan AC"},{"initials":"M","lastname":"Yarmarkovich","name":"Yarmarkovich M"},{"initials":"S","lastname":"Nerli","name":"Nerli S"},{"initials":"K","lastname":"Yamaguchi","name":"Yamaguchi K"},{"initials":"AA","lastname":"Madejska","name":"Madejska AA"},{"initials":"S","lastname":"Nguyen","name":"Nguyen S"},{"initials":"S","lastname":"Tripathi","name":"Tripathi S"},{"initials":"JM","lastname":"Maris","name":"Maris JM"},{"initials":"SR","lastname":"Salama","name":"Salama SR"},{"initials":"D","lastname":"Haussler","name":"Haussler D"},{"initials":"NG","lastname":"Sgourakis","name":"Sgourakis NG"}],"identifier":[{"id":"10.3389/fimmu.2018.00099","type":"doi"},{"id":"29441070","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"Front Immunol","name":""},"pages":["99"],"title":"A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations.","type":"article","url":"http://journal.frontiersin.org/article/10.3389/fimmu.2018.00099/full","volume":["9"],"year":[2018]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"1.70","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/5txs"},"rcsb":{"url":"https://www.rcsb.org/structure/5txs"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-B*15:01 binding \"AQDIYRASY\" at 1.70Å resolution","unique_chain_count":3}}