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Probing Molecular Interactions within Class II MHC A(q)/Glycopeptide/T-Cell Receptor Complexes Associated with Collagen-Induced Arthritis.

Andersson, Ida; Dzhambazov, Balik LU ; Holmdahl, Rikard LU ; Linusson, Anna and Kihlberg, Jan (2007) In Journal of Medicinal Chemistry 50(23). p.5627-5643
Abstract
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 A(q) molecule. We report a comparative 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 Ala(261) and Gly(262) 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 A(q) molecule, and the results were interpreted in view of the... (More)
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 A(q) molecule. We report a comparative 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 Ala(261) and Gly(262) 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 A(q) molecule, and the results were interpreted in view of the A(q)/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 A(q)/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggest possibilities for new vaccination approaches. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
50
issue
23
pages
5627 - 5643
publisher
American Chemical Society (ACS)
external identifiers
  • wos:000250809300017
  • scopus:36148963636
ISSN
1520-4804
DOI
10.1021/jm0705410
language
English
LU publication?
yes
id
ff9c13fc-0399-4e86-9d50-4b67b44244ba (old id 608461)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17944452&dopt=Abstract
date added to LUP
2009-07-10 14:53:55
date last changed
2017-04-09 03:39:33
@article{ff9c13fc-0399-4e86-9d50-4b67b44244ba,
  abstract     = {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 A(q) molecule. We report a comparative 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 Ala(261) and Gly(262) 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 A(q) molecule, and the results were interpreted in view of the A(q)/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 A(q)/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggest possibilities for new vaccination approaches.},
  author       = {Andersson, Ida and Dzhambazov, Balik and Holmdahl, Rikard and Linusson, Anna and Kihlberg, Jan},
  issn         = {1520-4804},
  language     = {eng},
  number       = {23},
  pages        = {5627--5643},
  publisher    = {American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Probing Molecular Interactions within Class II MHC A(q)/Glycopeptide/T-Cell Receptor Complexes Associated with Collagen-Induced Arthritis.},
  url          = {http://dx.doi.org/10.1021/jm0705410},
  volume       = {50},
  year         = {2007},
}