title: Covalent HLA-B27/peptide complex induced by specific recognition of an aziridine mimic of arginine.
abstract: The class I major histocompatibility complex (MHC) glycoprotein HLA-B27 binds short peptides containing arginine at peptide position 2 (P2). The HLA-B27/peptide complex is recognized by T cells both as part of the development of the repertoire of T cells in the cellular immune system and during activation of cytotoxic T cells. Based on the three-dimensional structure of HLA-B27, we have synthesized a ligand with an aziridine-containing side chain designed to mimic arginine and to bind covalently in the arginine-specific P2 pocket of HLA-B27. Using tryptic digestion followed by mass spectrometry and amino acid sequencing, the aziridine-containing ligand is shown to alkylate specifically cysteine 67 of HLA-B27. Neither free cysteine in solution nor an exposed cysteine on a class II MHC molecule can be alkylated, showing that specific recognition between the anchor side-chain pocket of an MHC class I protein and the designed ligand (propinquity) is necessary to induce the selective covalent reaction with the MHC class I molecule.
authors.affiliation: Department of Chemistry, Harvard University, Cambridge, MA 02138, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Weiss
authors.forename: R J
authors.initials: RJ
authors.lastname: Valentekovich
authors.forename: E J
authors.initials: EJ
authors.lastname: Collins
authors.forename: D N
authors.initials: DN
authors.lastname: Garboczi
authors.forename: W S
authors.initials: WS
authors.lastname: Lane
authors.forename: S L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: D C
authors.initials: DC
authors.lastname: Wiley
mesh_terms: D000345:Affinity Labels / Q000737:chemistry; D001120:Arginine / Q000031:analogs & derivatives*; D001388:Aziridines / Q000737:chemistry*; D001665:Binding Sites; D002942:Circular Dichroism; D015796:HLA-B27 Antigen / Q000737:chemistry*; D015798:HLA-DR1 Antigen / Q000378:metabolism; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding; D013816:Thermodynamics
chemical_list: D000345:Affinity Labels; D001388:Aziridines; D015796:HLA-B27 Antigen; D015798:HLA-DR1 Antigen; D008024:Ligands; D010455:Peptides; D001120:Arginine