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Small molecules containing hetero-bicyclic ring systems compete with UDP-Glc for binding to WaaG glycosyltransferase
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University. (Göran Widmalm)
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Karina Persson)
Institute of Chemistry, University of Luebeck. (Thomas Peters)
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University. (Göran Widmalm)
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2012 (English)In: Glycoconjugate Journal, ISSN 0282-0080, E-ISSN 1573-4986, Vol. 29, no 7, 491-502 p.Article in journal (Refereed) Published
Abstract [en]

The α-1,3-glucosyltransferase WaaG is involved in the synthesis of the core region of lipopolysaccharides in E. coli. A fragment-based screening for inhibitors of the WaaG glycosyltrasferase donor site has been performed using NMR spectroscopy. Docking simulations were performed for three of the compounds of the fragment library that had shown binding activity towards WaaG and yielded 3D models for the respective complexes. The three ligands share a hetero-bicyclic ring system as a common structural motif and they compete with UDP-Glc for binding. Interestingly, one of the compounds promoted binding of uridine to WaaG, as seen from STD NMR titrations, suggesting a different binding mode for this ligand. We propose these compounds as scaffolds for the design of selective high-affinity inhibitors of WaaG. Binding of natural substrates, enzymatic activity and donor substrate selectivity were also investigated by NMR spectroscopy. Molecular dynamics simulations of WaaG were carried out with and without bound UDP and revealed structural changes compared to the crystal structure and also variations in flexibility for some amino acid residues between the two WaaG systems studied.

Place, publisher, year, edition, pages
Springer, 2012. Vol. 29, no 7, 491-502 p.
Keyword [en]
Glycosyltransferase, Inhibitor, NMR, Molecular modeling, Screening
National Category
Organic Chemistry
Research subject
Organic Chemistry; biological chemistry
URN: urn:nbn:se:umu:diva-58008DOI: 10.1007/s10719-012-9411-4OAI: diva2:546306
Structural and functional characterization of glycosyltransferases
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2012-08-23 Created: 2012-08-23 Last updated: 2012-10-18Bibliographically approved

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