Probing molecular interactions within class II MHC Aq/glycopeptide/T-cell receptor complexes associated with collagen-induced arthritis.
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 psi[COCH2], psi[CH2NH2+], and psi[(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.
Andersson
Ida E
IE
Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Dzhambazov
Balik
B
Holmdahl
Rikard
R
Linusson
Anna
A
Kihlberg
Jan
J
D000409:Alanine / Q000737:chemistry; D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology*; D001667:Binding, Competitive; D018920:Coculture Techniques; D024043:Collagen Type II / Q000737:chemistry*; D005998:Glycine / Q000737:chemistry; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000378:metabolism; D006825:Hybridomas; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000378:metabolism
D024043:Collagen Type II; D006020:Glycopeptides; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D000409:Alanine; D005998:Glycine