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histocompatibility complex (MHC) class I molecules present short peptide ligands on the cell surface for interrogation by cytotoxic CD8+ T cells. MHC class I complexes presenting tumor-associated peptides such as neoantigens represent key targets of cancer immunotherapy approaches currently in development, making them important for efficacy and safety screenings. Without peptide ligand, MHC class I complexes are unstable and decay quickly, making the production of soluble monomers for analytical purposes labor intensive. We have developed a disulfide-stabilized HLA-A*02:01 molecule that is stable without peptide but can form peptide-MHC complexes (pMHCs) with ligands of choice in a one-step loading procedure. We illustrate the similarity between the engineered mutant and the wild-type molecule with respect to affinity of wild-type or affinity-matured T cell receptors (TCRs) and present a crystal structure corroborating the binding kinetics measurements. In addition, we demonstrate a high-throughput binding kinetics measurement platform to analyze the binding characteristics of bispecific TCR (bsTCR) molecules against diverse pMHC libraries produced with the disulfide-stabilized HLA-A*02:01 molecule. We show that bsTCR affinities for pMHCs are indicative of in vitro function and generate a bsTCR binding motif to identify potential off-target interactions in the human proteome. These findings showcase the potential of the platform and the engineered HLA-A*02:01 molecule in the emerging field of pMHC-targeting biologics.","bibjson":{"author":[{"initials":"A","lastname":"Moritz","name":"Moritz A"},{"initials":"R","lastname":"Anjanappa","name":"Anjanappa R"},{"initials":"C","lastname":"Wagner","name":"Wagner C"},{"initials":"S","lastname":"Bunk","name":"Bunk S"},{"initials":"M","lastname":"Hofmann","name":"Hofmann M"},{"initials":"G","lastname":"Pszolla","name":"Pszolla G"},{"initials":"A","lastname":"Saikia","name":"Saikia A"},{"initials":"M","lastname":"Garcia-Alai","name":"Garcia-Alai M"},{"initials":"R","lastname":"Meijers","name":"Meijers R"},{"initials":"HG","lastname":"Rammensee","name":"Rammensee HG"},{"initials":"S","lastname":"Springer","name":"Springer S"},{"initials":"D","lastname":"Maurer","name":"Maurer D"}],"identifier":[{"id":"10.1126/sciimmunol.aav0860","type":"doi"},{"id":"31324691","type":"pubmed"}],"issue":["37"],"journal":{"iso_abbreviation":"Sci Immunol","name":""},"pages":[null],"title":"High-throughput peptide-MHC complex generation and kinetic screenings of TCRs with peptide-receptive HLA-A*02:01 molecules.","type":"article","url":"https://www.science.org/doi/10.1126/sciimmunol.aav0860","volume":["4"],"year":[2019]},"in_pmc":"N","in_pmce":"N","open_access":"N"},"resolution":"2.50","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/6q3s"},"rcsb":{"url":"https://www.rcsb.org/structure/6q3s"},"stcrdab":{"url":"http://opig.stats.ox.ac.uk/webapps/stcrdab/StrViewer?pdb=6q3s"}},"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":"TRBV6"},"mhc_type":"class_i","pdb_code":"6q3s"},"title":"HLA-A*02:01 presenting \"SLLMWITQV\" to Alpha/Beta T cell receptor at 2.50Å resolution","unique_chain_count":5}}