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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":"2.59","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/5vz5"},"rcsb":{"url":"https://www.rcsb.org/structure/5vz5"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-B*15:01 binding \"AQDIYRASYY\" at 2.59Å resolution","unique_chain_count":3}}