Probing Molecular Interactions within Class II MHC Aq/Glycopeptide/T-Cell Receptor Complexes Associated with Collagen-Induced Arthritis

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• 作者：Ida E. Andersson ; Balik Dzhambazov ; Rikard Holmdahl ; Anna Linusson ; Jan Kihlberg
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 15, 2007
• 年：2007
• 卷：50
• 期：23
• 页码：5627 - 5643
• 全文大小：568K
• 年卷期：v.50,no.23(November 15, 2007)
• ISSN：1520-4804

文摘

T cells obtained in a mouse model for rheumatoid arthritis are activated by a glycopeptide fragment fromrat type II collagen (CII) bound to the class II major histocompatibility complex A^q molecule. We report acomparative model of A^q 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 selectedfor replacement with [COCH₂], [CH₂NH₂⁺], and [(E)-CH=CH] isosteres. Ala-Gly isostere buildingblocks were then synthesized and introduced in CII260-267 and CII259-273 glycopeptides. The modifiedglycopeptides were evaluated for binding to the A^q molecule, and the results were interpreted in view of theA^q/glycopeptide model. Moreover, recognition by a panel of T-cell hybridomas revealed high sensitivityfor the backbone modifications. These studies contribute to the understanding of the interactions in theternary A^q/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggestpossibilities for new vaccination approaches.