PhD Research Project: Structural studies of mycobacterial cell wall synthesis and regulation

The cell wall of Mycobacterium tuberculosis, the agent causing tuberculosis, plays key roles in virulence and contributes crucially to persistence of the pathogen in the host. My laboratory is involved in X-ray crystallographic studies that focus on enzymes and regulatory proteins involved in synthesising components of the mycobacterial cell wall, a subset of which constitute potential or established TB drug targets. While X-ray crystallography is the primary experimental tool, we combine structural studies with the biophysical and biochemical characterisation of targets.

We recently determined the structure of the transcriptional regulator M. tuberculosis EmbR (Alderwick et al., 2006), a DNA binding protein involved in a Ser/Thr-kinase dependent regulatory pathway of the immunomodulatory glycolipd lipoarabinomannan. EmbR contains a C-terminal FHA-domain, which binds to Thr-phosphorylated residues in a sequence-specific context, and, following Thr-phosphorylation, is thought to repress or activate transcription of membrane-embedded arabinofuranosyltransferases.

PIM (phosphatidylinositol mannoside) are precursors of lipoarabinomannan. Their synthesis is iniated in the cytoplasm by attaching mannan saccharides to the inositol moiety of phosphatidylinositol. Very recently, we determined the structure of mannosyltransferase PimB’, which attaches the second mannose residue in PIM synthesis (Batt et al., 2010). Through a mutational study that was guided by our structure we were able to define the structural determinants of regio-specificity of mannosyl transfer.

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To find out more about studying for a PhD at the University of Birmingham, including full details of the research undertaken in each school, the funding opportunities for each subject, and guidance on making your application, you can now order your copy of the new Doctoral Research Prospectus, at: http://www.birmingham.ac.uk/students/drp.aspx
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Please find additional funding text below. For further funding details, please see the ‘Funding’ section.
The School of Biosciences offers a number of UK Research Council (e.g. BBSRC, NERC) PhD studentships each year. Fully funded research council studentships are normally only available to UK nationals (or EU nationals resident in the UK) but part-funded studentships may be available to EU applicants resident outside of the UK. The deadline for applications for research council studentships is 31 January each year.

Each year we also have a number of fully funded Darwin Trust Scholarships. These are provided by the Darwin Trust of Edinburgh and are for non-UK students wishing to undertake a PhD in the general area of Molecular Microbiology. The deadline for this scheme is also 31 January each year.

Funding Notes

All applicants should indicate in their applications how they intend to fund their studies. We have a thriving community of international PhD students and encourage applications at any time from students able to find their own funding or who wish to apply for their own funding (e.g. Commonwealth Scholarship, Islamic Development Bank).

The postgraduate funding database provides further information on funding opportunities available http://www.birmingham.ac.uk/postgraduate/funding/FundingFilter.aspx and further information is also available on the School of Biosciences website http://www.birmingham.ac.uk/schools/biosciences/courses/postgraduate/phd.aspx
 

References

Selected publications:

Batt SM, Jabeen T, Mishra AK, Veerapen N, Krumbach K, Eggeling L, Besra GS, Fütterer K (2010) Acceptor Substrate Discrimination in Phosphatidyl-myo-inositol Mannoside Synthesis:Structural and mutational analysis of mannosyltransferase Corynebacterium glutamicum PimB'. J Biol Chem. 285:37741-52.

Brown AK, Taylor RC, Bhatt A, Fütterer K, Besra GS (2009) Platensimycin activity against mycobacterial beta-ketoacyl-ACP synthases.
PLoS One. 4:e6306.

Meng G, Fütterer K. (2008) Donor substrate recognition in the raffinose-bound E342A mutant of fructosyltransferase Bacillus subtilis levansucrase. BMC Struct Biol. 8:16

Brown AK, Meng G, Ghadbane H, Scott DJ, Dover LG, Nigou J, Besra GS, Fütterer K. (2007) Dimerization of inositol monophosphatase Mycobacterium tuberculosis SuhB is not constitutive, but induced by binding of the activator Mg2+. BMC Struct. Biol 7:55.

Alderwick LJ, Molle V, Kremer L, Cozzone AJ, Dafforn TR, Besra GS, Fütterer K (2006) Molecular structure of EmbR, a response element of Ser/Thr kinase signaling in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 103:2558-63.

Millard TH, Bompard G, Heung MY, Dafforn TR, Scott DJ, Machesky LM, Fütterer K (2005) Structural basis of filopodia formation induced by the IRSp53/MIM homology domain of human IRSp53. EMBO J. 24:240-50.

G Meng, K Fütterer (2003) "Structural framework for fructosyltransfer in Bacillus subtilis levansucrase" Nat Struct Biol 10, 935 - 941