Structural studies on gene regulation, bacterial virulence and multidrug resistance; drug design 

A major aim of the Brennan laboratory is to understand the structural mechanisms of protein-DNA recognition and gene regulation. To pursue this goal we have solved the crystal structures of a variety of transcription regulators such as the E. coli Purine repressor and mammalian CREB bZIP. We have also determined drug and DNA-bound structures of BmrR, a B. subtilis multidrug transporter (mdt) gene activator, and QacR, which represses two S. aureus mdt genes, and MtaN, a global regulator of mdt genes in B. subtilis.

We are continuing a multipronged approach, which utilizes the tools of molecular biology, biochemistry and x-ray crystallography, to elucidate fully the structural mechanisms of multidrug binding with the longer-term goal of developing novel antibacterial chemotherapeutics. In addition, we are trying to discover new drugs against parasitic protozoa by combining structural and biochemical data with computational methods. Our targets include enzymes of the purine and pyrimidine salvage pathways, such as the uracil phosphoribosyltransferase and adenosine kinase from Toxoplasma gondii, the causative agent of toxoplasmosis. We are pursuing the structures of transition-state intermediates and site-directed mutants of these enzymes to understand their catalytic mechanisms and substrate specificities and to accomplish our drug design objectives. 
 
 
 

Recent Publications:

1. Moller T., Franch T., Hojrup P., Keene D.R., Bachinger H.P., Brennan R.G., and Valentin-Hansen P. Hfq. A Bacterial Sm-like Protein that Mediates RNA-RNA Interaction. Mol. Cell 9(1):23-30 (2002).

2. Schumacher M.A., Bashor C.J., Song M.H., Otsu K., Zhu S., Parry R.J., Ullman B., and Brennan R.G. The structural mechanism of GTP stabilized oligomerization and catalytic activation of the Toxoplasma gondii uracil phosphoribosyltransferase. Proc. Natl. Acad. Sci. USA 99(1):78-83 (2002).

3. Schumacher M.A., Miller M.C., Grkovic S., Brown M.H., Skurray R.A., and Brennan R.G. Structural mechanisms of QacR induction and multidrug recognition. Science 294(5549):2158-63 (2001). 

4. Schumacher, M.A., Pearson, R.F., Moller, T, Valentin-Hansen, P and Brennan, R.G. Structures of the pleiotropic translational regulator Hfq and an Hfq-RNA complex: A bacterial Sm-like protein. EMBO J. 21:3546-3556 (2002).

5. Schumacher, M.A., Miller, M.C., Grkovic, S. , Brown, M.H., Skurray, R.A. and Brennan, R.G. Structural basis for cooperative DNA binding by two dimers of the multidrug-binding protein QacR. EMBO J. 21:1210-1218 (2002).