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(E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
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2011 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 133, no 36, 14368-14378 p.Article in journal (Refereed) Published
Abstract [en]

The structural basis for antigen presentation by class II major histocompatibility complex (MHC) proteins to CD4(+) T-cells is important for understanding and possibly treating autoimmune diseases. In the work described in this paper, (E)-alkene and ethylene amide-bond isosteres were used to investigate the effect of removing hydrogen-bonding possibilities from the CII259-270 glycopeptide, which is bound by the arthritis-associated murine A(q) class II MHC protein. The isostere-modified glycopeptides showed varying and unexpectedly large losses of A(q) binding that could be linked to the dynamics of the system. Molecular dynamics (MD) simulations revealed that the backbone of CII259-270 and the A(q) protein are able to form up to 11 hydrogen bonds, but fewer than this number are present at any one time. Most of the strong hydrogen-bond interactions were formed by the N-terminal part of the glycopeptide, i.e., in the region where the isosteric replacements were made. The structural dynamics also revealed that hydrogen bonds were strongly coupled to each other; the loss of one hydrogen-bond interaction had a profound effect on the entire hydrogen-bonding network. The A(q) binding data revealed that an ethylene isostere glycopeptide unexpectedly bound more strongly to A(q) than the corresponding (E)-alkene, which is in contrast to the trend observed for the other isosteres. Analysis of the MD trajectories revealed that the complex conformation of this ethylene isostere was structurally different and had an altered molecular interaction pattern compared to the other A(q)/glycopeptide complexes. The introduced amide-bond isosteres also affected the interactions of the glycopeptide/A(q) complexes with T-cell receptors. The dynamic variation of the patterns and strengths of the hydrogen-bond interactions in the class II MHC system is of critical importance for the class II MHC/peptide/TCR signaling system.

Place, publisher, year, edition, pages
American Chemical Society , 2011. Vol. 133, no 36, 14368-14378 p.
National Category
Chemical Sciences
URN: urn:nbn:se:umu:diva-42072DOI: 10.1021/ja2038722OAI: diva2:408485
Available from: 2011-04-05 Created: 2011-04-05 Last updated: 2011-10-20Bibliographically approved
In thesis
1. Modified Glycopeptides Targeting Rheumatoid Arthritis: Exploring molecular interactions in class II MHC/glycopeptide/T-cell receptor complexes
Open this publication in new window or tab >>Modified Glycopeptides Targeting Rheumatoid Arthritis: Exploring molecular interactions in class II MHC/glycopeptide/T-cell receptor complexes
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that leads to degradation of cartilage and bone mainly in peripheral joints. In collagen-induced arthritis (CIA), a mouse model for RA, activation of autoimmune CD4+ T cells depends on a molecular recognition system where T-cell receptors (TCRs) recognize a complex between the class II MHC Aq protein and CII259-273, a glycopeptide epitope from type II collagen (CII). Interestingly, vaccination with the Aq/CII259-273 complex can relieve symptoms and cause disease regression in mice. This thesis describes the use of modified glycopeptides to explore interactions important for binding to the Aq protein and recognition by autoimmune T-cell hybridomas obtained from mice with CIA.

The CII259-273 glycopeptide was modified by replacement of backbone amides with different amide bond isosteres, as well as substitution of two residues that anchor the glycopeptide in prominent pockets in the Aq binding site. A three-dimensional structure of the Aq/glycopeptide complex was modeled to provide a structural basis for interpretation of the modified glycopeptide’s immunological activities. Overall, it was found that the amide bond isosteres affected Aq binding more than could be explained by the static model of the Aq/glycopeptide complex. Molecular dynamics (MD) simulations, however, revealed that the introduced amide bond isosteres substantially altered the hydrogen-bonding network formed between the N-terminal 259-265 backbone sequence of CII259-273 and Aq. These results indicated that the N-terminal hydrogen-bonding interactions follow a cooperative model, where the strength and presence of individual hydrogen bonds depended on the neighboring interactions.

The two important anchor residues Ile260 and Phe263 were investigated using a designed library of CII259-273 based glycopeptides with substitutions by different (non-)natural amino acids at positions 260 and 263. Evaluation of binding to the Aq protein showed that there was scope for improvement in position 263 while Ile was preferred in position 260. The obtained SAR understanding provided a valuable basis for future development of modified glycopeptides with improved Aq binding. Furthermore, the modified glycopeptides elicited varying T-cell responses that generally could be correlated to their ability to bind to Aq. However, in several cases, there was a lack of correlation between Aq binding and T-cell recognition, which indicated that the interactions with the TCRs were determined by other factors, such as presentation of altered epitopes and changes in the kinetics of the TCR’s interaction with the Aq/glycopeptide complex.

Several of the modified glycopeptides were also found to bind well to the human RA-associated DR4 protein and elicit strong responses with T-cell hybridomas obtained from transgenic mice expressing DR4 and the human CD4 co-receptor. This encourages future investigations of modified glycopeptides that can be used to further probe the MHC/glycopeptide/TCR recognition system and that also constitute potential therapeutic vaccines for treatment of RA. As a step towards this goal, three modified glycopeptides presented in this thesis have been identified as candidates for vaccination studies using the CIA mouse model.

Place, publisher, year, edition, pages
Umeå: Umeå universitet. Kemiska institutionen, 2011. 65 p.
Major histocompatibility complex, class II MHC, T-cell receptor, rheumatoid arthritis, collagen-induced arthritis, glycopeptide, amide bond isostere, comparative modeling, rational design, molecular docking, molecular dynamics simulation, statistical molecular design
National Category
Organic Chemistry
Research subject
Organic Chemistry; Biorganic Chemistry; läkemedelskemi
urn:nbn:se:umu:diva-42082 (URN)978-91-7459-173-6 (ISBN)
Public defence
2011-04-29, KBC-huset, KB3B1, Umeå Universitet, Umeå, 10:00 (English)
Available from: 2011-04-08 Created: 2011-04-05 Last updated: 2011-04-11Bibliographically approved

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Andersson, Ida E.Kihlberg, JanLinusson, Anna
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