Contribution of peptide backbone atoms to binding of an antigenic peptide to class I major histocompatibility complex molecule.
Antigenic peptides are thought to bind to class I major histocompatibility complex (MHC) molecules through three modes of interaction: van der Waals interaction and, to a lesser extent, hydrogen bonding of anchor side chain atoms to residues comprising the binding pockets of the MHC molecule; hydrogen bonding of N- and C-termini to residues at the ends of the binding groove; and hydrogen bonding of peptide backbone atoms to residues lining the binding groove. To dissect the relative contribution of each of these interactions to class I MHC-peptide stability, a retro inverso (RI) analog of VSV-8. an H-2Kb restricted cytotoxic T lymphocyte (CTL) epitope and terminally modified variants of both VSV-8 and RI VSV-8 were synthesized and their ability to target H-2Kb bearing cells for CTL mediated lysis was compared. None of RI VSV-8 analogs elicited lysis of target cells by CTL specific for VSV-8 nor did they appear to compete with the native peptide for binding to H-2Kb. In contrast, terminally modified VSV-8 peptides elicited target lysis. These findings suggest that side chain topochemistry of the peptide is insufficient for stable peptide binding to H-2Kb; rather, hydrogen bonding of the peptide backbone atoms to H-2Kb side chain atoms appears to play a major role in the stability of the complex. Computer modeling confirmed that none of the RI analogs participate in the extensive hydrogen bonding network between the peptide backbone and the MHC molecule seen in the native structure.
Saito
N G
NG
Department of Microbiology and The Eldridge Reeves Johnson Foundation for Molecular Biophysics, University of Pennsylvania, Philadelphia 19104-6076, USA.
Paterson
Y
Y
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000941:Antigens / Q000737:chemistry / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000941:Antigens; D015395:Histocompatibility Antigens Class I; D010455:Peptides