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Glycoconjugate Journal

, Volume 29, Issue 7, pp 491–502 | Cite as

Small molecules containing hetero-bicyclic ring systems compete with UDP-Glc for binding to WaaG glycosyltransferase

  • Jens Landström
  • Karina Persson
  • Christoph Rademacher
  • Magnus Lundborg
  • Warren Wakarchuk
  • Thomas Peters
  • Göran WidmalmEmail author
Article

Abstract

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.

Keywords

Glycosyltransferase Inhibitor NMR Molecular modeling Screening 

Notes

Acknowledgments

This work was supported by grants from the Swedish Research Council, The Knut and Alice Wallenberg Foundation, The Åke Wiberg Foundation, Fonds der Chemischen Industrie, and Deutscher Akademischer Austausch Dienst. We thank Gunter Stier, EMBL, Germany for cloning vectors.

Supplementary material

10719_2012_9411_MOESM1_ESM.doc (272 kb)
ESM 1 (DOC 271 kb)

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Jens Landström
    • 1
  • Karina Persson
    • 2
  • Christoph Rademacher
    • 3
  • Magnus Lundborg
    • 1
  • Warren Wakarchuk
    • 4
  • Thomas Peters
    • 3
  • Göran Widmalm
    • 1
    Email author
  1. 1.Department of Organic Chemistry, Arrhenius LaboratoryStockholm UniversityStockholmSweden
  2. 2.Department of ChemistryUmeå UniversityUmeåSweden
  3. 3.Institute of ChemistryUniversity of LuebeckLuebeckGermany
  4. 4.National Research Council of CanadaInstitute for Biological SciencesOttawaCanada

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