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Uciechowska, Urszula
Publications (2 of 2) Show all publications
Lindgren, C., Andersson, I. E., Berg, L., Dobritzsch, D., Ge, C., Haag, S., . . . Linusson, A. (2015). Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A(q)/glycopeptide complexes. Organic and biomolecular chemistry, 13(22), 6203-6216
Open this publication in new window or tab >>Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A(q)/glycopeptide complexes
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2015 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 22, p. 6203-6216Article in journal (Refereed) Published
Abstract [en]

Class II major histocompatibility complex (MHC) proteins are involved in initiation of immune responses to foreign antigens via presentation of peptides to receptors of CD4(+) T-cells. An analogous presentation of self-peptides may lead to autoimmune diseases, such as rheumatoid arthritis (RA). The glycopeptide fragment CII259-273, derived from type II collagen, is presented by A(q) MHCII molecules in the mouse and has a key role in development of collagen induced arthritis (CIA), a validated model for RA. We have introduced hydroxyethylene amide bond isosteres at the Ala(261)-Gly(262) position of CII259-273. Biological evaluation showed that A(q) binding and T cell recognition were dramatically reduced for the modified glycopeptides, although static models predicted similar binding modes as the native type II collagen fragment. Molecular dynamics (MD) simulations demonstrated that introduction of the hydroxyethylene isosteres disturbed the entire hydrogen bond network between the glycopeptides and A(q). As a consequence the hydroxyethylene isosteric glycopeptides were prone to dissociation from A(q) and unfolding of the beta(1)-helix. Thus, the isostere induced adjustment of the hydrogen bond network altered the structure and dynamics of A(q)/glycopeptide complexes leading to the loss of A(q) affinity and subsequent T cell response.

National Category
Organic Chemistry
urn:nbn:se:umu:diva-106519 (URN)10.1039/c5ob00395d (DOI)000355489600011 ()25960177 (PubMedID)
Available from: 2015-07-15 Created: 2015-07-14 Last updated: 2018-06-07Bibliographically approved
Andersson, C. D., Karlberg, T., Ekblad, T., Lindgren, A. E., Thorsell, A.-G., Spjut, S., . . . Linusson, A. (2012). Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening. Journal of Medicinal Chemistry, 55(17), 7706-7718
Open this publication in new window or tab >>Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening
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2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 17, p. 7706-7718Article in journal (Refereed) Published
Abstract [en]

The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyses the transfer of ADP-ribose units onto substrate proteins, using nicotinamide adenine dinucleotide (NAD(+)) as a co-substrate. They have a documented role in chromatin remodelling and DNA repair; and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. Using virtual screening we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.

National Category
Chemical Sciences
urn:nbn:se:umu:diva-57906 (URN)10.1021/jm300746d (DOI)22823910 (PubMedID)
Available from: 2012-08-21 Created: 2012-08-21 Last updated: 2018-06-08Bibliographically approved

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