Computer design of T-cell agonist or antagonist glycopeptides: the effect of sugar identity and anomeric configuration on MHC binding.
The improved chemical and biological properties of synthetic glycopeptides over peptides suggest their use as T cell agonists or antagonists. Recently, we prepared glycopeptide analogues of major T helper cell epitopic peptides corresponding to rabies virus proteins, and experimentally characterized their ability to bind to MHC class II proteins and stimulate T cell clones to rabies virus. In the current study, we investigated these MHC: peptide interactions by molecular modeling. We obtained structural support for our finding concerning the anomeric specificity of MHC with binding. While alpha-linked glycopeptides can bind to MHC without major alterations in the spatial arrangements and hydrogen bonding pattern of class II-peptide binding, the binding of beta-linked glycopeptides is considerably less favorable due to steric and columbic conflicts. Depending on where the saccharides are positioned along the peptide sequence, the MHC: glycopeptide complex may or may not produce the surface profile required for successful T cell receptor interaction. Application of this approach to other antigenic stimuli offers a good model to "dial in" the necessary sugar identity, length and anomeric configuration, as well as promising amino acid mutation sites, for successful design of T cell agonist or antagonist glycopeptides.
Prammer
K V
KV
Wistar Institute, Philadelphia, PA 19104, USA.
Ertl
H C
HC
Otvos
L
L
D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D003198:Computer Simulation; D000939:Epitopes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015798:HLA-DR1 Antigen / Q000737:chemistry* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009698:Nucleoproteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D011820:Rabies virus / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D016415:Sequence Alignment
D000956:Antigens, Viral; D000939:Epitopes; D006023:Glycoproteins; D015798:HLA-DR1 Antigen; D036341:Intercellular Signaling Peptides and Proteins; D009698:Nucleoproteins; D011948:Receptors, Antigen, T-Cell; C090319:peptide 31D; C090318:peptide VF13N