Richard G. Brennan, Ph.D. 1984, University of Wisconsin - Madison The University of Texas M. D. Anderson Cancer Center Department of Biochemistry and Molecular Biology Contact Information

Research Interests:

• Multidrug resistance, protein-nucleic interaction, regulation of gene expression
• Oxidative stress responses
• Protein-ligand interaction, toxin-antitoxin structure and function
• Macromolecular crystallography
  

The research in my laboratory focuses on understanding the structural mechanisms that underlie multiple biological processes. One major aspect of the laboratory’s research is to delineate the mechanisms by which single proteins are able to recognize and bind multiple, chemically and structurally dissimilar drugs, i.e., how proteins contribute to multidrug resistance and multidrug tolerance. Just how a single protein can bind multiple, structurally and chemically dissimilar compounds is a fascinating problem. As part of this interest, we employ biochemical, molecular biological and crystallographic tools to study transcription factors that are multidrug binding proteins. In addition to their multidrug binding properties, we are very interested in understanding their mechanisms of gene regulation, i.e., their DNA binding properties and mechanisms of induction. In a related light, we also study how global regulators such as CcpA, TnrA and Hfq respond to a variety of metabolic cues in order to carry out their gene regulatory functions. Another major research interest is the structural response by transcription factors to a variety of oxidative stresses such that the cell is able to survive the presence of reactive oxygen species, such as organic hydroperoxides, and to overcome disulphide stress. We are developing a strong interest in bacterial “toxin-antitoxin” systems, which in reality are sensors of different cellular stresses that result in the release of the “toxin”, which to date have been shown to be proteins with a wide variety of catalytic properties, to effect the appropriate response. Finally, we are taking on a slew of new projects that deal with the underlying mechanisms of oncogenesis. These studies involve structural studies on protein-protein complexes, the dysregulation of which lead to improper signal transduction and uncontrolled cellular proliferation.

A tutorial in my laboratory would combine biochemical and crystallographic methods in order to study the structure-function relationships of one of these proteins. Depending upon which system is chosen, a tutorial student would learn how to create one or more site-directed mutants, purify the resulting protein(s), characterize the biochemical function(s) of selected mutants, e.g., their DNA or ligand binding properties, set up crystallization experiments, and if time permitting collect x-ray intensity data and begin the process of structure determination and refinement.

Publications

Program Affiliation:

Program in Genes and Development