title: The structure of the human allo-ligand HLA-B*3501 in complex with a cytochrome p450 peptide: steric hindrance influences TCR allo-recognition.
abstract: Virus-specific T cell populations have been implicated in allo-recognition. The subdominant T cell receptor JL12 recognizes both HLA-B*0801 presenting the Epstein-Barr virus-derived peptide FLRGRAYGL and also HLA-B*3501 presenting the cytochrome p450 self peptide KPIVVLHGY. This cross-reactivity could promote the rejection of HLA-B*3501-positive cells in Epstein-Barr virus-exposed HLA-B*0801 recipients. LC13, the dominant TCR against the HLA-B*0801:FLRGRAYGL complex, fails to recognize HLA-B*3501:KPIVVLHGY. We report the 1.75-Angstrom resolution crystal structure of the human allo-ligand HLA-B*3501:KPIVVLHGY. Similarities between this structure and that of HLA-B*0801:FLRGRAYGL may facilitate cross-recognition by JL12. Moreover, the elevated peptide position in HLA-B*3501:KPIVVLHGY would provide steric hindrance to LC13, preventing it from interacting in the manner in which it interacts with HLA-B*0801:FLRGRAYGL. These findings are relevant to understanding the basis of T cell cross-reactivity in allo-recognition, optimal transplant donor-recipient matching and developing specific molecular inhibitors of allo-recognition.
authors.affiliation: Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hourigan
authors.forename: Maria
authors.initials: M
authors.lastname: Harkiolaki
authors.forename: Neil A
authors.initials: NA
authors.lastname: Peterson
authors.forename: John I
authors.initials: JI
authors.lastname: Bell
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: Chris A
authors.initials: CA
authors.lastname: O'Callaghan
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D015235:HLA-B Antigens / Q000737:chemistry* / Q000378:metabolism; D015797:HLA-B35 Antigen; D006801:Humans; D007519:Isoantigens / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D015235:HLA-B Antigens; C500431:HLA-B*35:01 antigen; D015797:HLA-B35 Antigen; D007519:Isoantigens; D008024:Ligands; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D003577:Cytochrome P-450 Enzyme System