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Structure and function of Streptococcus pyogenes virulence factor biosynthesis

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  • Full or part time
    Dr Dorfmueller
  • Application Deadline
    No more applications being accepted

Project Description

The Helge Dorfmueller (HD) lab is a young lab in the dynamic and vibrant Division of Molecular Microbiology at the University of Dundee. HD’s research focus lies on understanding the molecular details of how the human-exclusive pathogen Streptococcus pyogenes (GAS) synthesises an abundant surface carbohydrate, involved into GAS virulence. GAS is a severe burden to human life, causing a range of mild and severe, invasive infections with high morbidity and mortality rates (> 500,000 death / per year). It is imperative that we identify and characterise new drug targets to develop more efficient antibiotics and to prevent a shortfall of antibiotics in the near future.
The student will conduct fundamental and interdisciplinary research. The project and research training involves molecular microbiology and glycobiology, including cloning, protein expression and purification from recombinant bacterial system. Functional characterisation of the enzymes will be carried out using a combination of bacterial genetics, synthetic biology, carbohydrate analysis and enzyme assay development [1]. In collaboration with the Mike Ferguson lab, the student will obtain expert training in carbohydrate purification and analysis, using biochemistry and mass-spectrometry [2]. The student will have the opportunity to learn protein crystallisation and high-resolution single crystal X-ray diffraction analysis. These structural studies will reveal detailed insights into the mechanism of catalysis of these novel enzymes. Furthermore, the student will be trained in inhibitor screening to identify the first chemical compounds that bind to the target enzyme. We pair enzymology with structural biology to investigate the kinetic properties of these compounds, which in combination provide the full basis for future structure-based drug design [3].

Funding Notes


References

[1] van der Beek, S. L., Le Breton, Y., Ferenbach, A. T., Chapman, R.N., van Aalten, D.M.F., Navratilova, I., Boons, G.J., McIver, K., van Sorge, N. M. and H.C. Dorfmueller; 'GacA is Essential for Group A Streptococcus and Defines a New Class of Monomeric dTDP-4-dehydrorhamnose Reductases (RmlD)', in print at Molecular Microbiology.
[2] Allen, S., Richardson, J.M., Mehlert, A and Ferguson, M.A.J. (2013) 'Structure of a complex phosphoglycan epitope from gp72 of Trypanosoma cruzi.' J. Biol. Chem. 288, 11093-11105.
[3] Dorfmueller, H.C., Borodkin, V.S., Schimpl, M., and van Aalten, D.M.F. (2009) 'GlcNAcstatins are nanomolar inhibitors of human O-GlcNAcase inducing cellular hyper-O-GlcNAcylation.' Biochem. J., 420(2), 221-7.

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