Probing molecular interactions within Class II MHC Aq/Glycopeptide/T-Cell Receptor Complexes associated with Collagen-Induced Arthritis
2007 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, no 23, 5627-5643 p.Article in journal (Refereed) Published
T cells obtained in a mouse model for rheumatoid arthritis are activated by a glycopeptide fragment from rat type II collagen (CII) bound to the class II major histocompatibility complex Aq molecule. We report a comparative model of Aq in complex with the glycopeptide CII260-267. This model was used in a structure-based design approach where the amide bond between Ala261 and Gly262 in the glycopeptide was selected for replacement with [COCH2], [CH2NH2+], and [(E)-CH=CH] isosteres. Ala-Gly isostere building blocks were then synthesized and introduced in CII260-267 and CII259-273 glycopeptides. The modified glycopeptides were evaluated for binding to the Aq molecule, and the results were interpreted in view of the Aq/glycopeptide model. Moreover, recognition by a panel of T-cell hybridomas revealed high sensitivity for the backbone modifications. These studies contribute to the understanding of the interactions in the ternary Aq/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggest possibilities for new vaccination approaches.
Place, publisher, year, edition, pages
2007. Vol. 50, no 23, 5627-5643 p.
IdentifiersURN: urn:nbn:se:umu:diva-17780DOI: doi:10.1021/jm0705410OAI: oai:DiVA.org:umu-17780DiVA: diva2:157453