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Small molecules containing hetero-bicyclic ring systems compete with UDP-Glc for binding to WaaG glycosyltransferase
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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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 alpha-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
2012. Vol. 29, no 7, 491-502 p.
Keyword [en]
Glycosyltransferase, Inhibitor, NMR, Molecular modeling, Screening
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:su:diva-81271DOI: 10.1007/s10719-012-9411-4ISI: 000308356000004OAI: diva2:560560
Swedish Research CouncilKnut and Alice Wallenberg Foundation


Available from: 2012-10-15 Created: 2012-10-15 Last updated: 2013-01-08Bibliographically approved

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Widmalm, Göran
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Department of Organic Chemistry
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