We study mechanisms required for the pathogenesis of infection and cancer and discover novel compounds to inhibit these mechanisms by using a combination of enzymology, structural biology and biophysical chemistry.
DNA Replication in Mycobacteria
Organisms from all kingdoms of life, including viruses, rely on timely and accurate DNA replication to propagate and preserve genetic information from parents to progeny. The genomic revolution in the last decade allowed us to study biological processes in a variety of pathogenic organisms. We study DNA replication mechanisms in pathogenic microorganisms such as Mycobacterium tuberculosis and explore novel approaches to discovery and development of molecules that inhibit these processes. These inhibitory molecules could be used as biochemical probes or further developed into novel anti-infectives.
Crystal structure of the N-terminal domain of M. tuberculosis DnaB helicase.
Biswas, T. and Tsodikov, O. V. (2008) FEBS J., 275, 3064-3071.
Mechanisms of Transcriptional Regulation
We are interested in the structure-function relationship of transcription factors, proteins that regulate (or dysregulate) transcription in all domains of life. While normally these transcription factors protect humans from cancer and other diseases, their genetic mutations (as with FLI1 shown in the figure) can reprogram the cell and cause cancer. A combination of structural and biochemical approaches is directed towards understanding transcription factor-driven mechanisms and towards developing agents preventing abnormal transcriptional regulation.
Transcription factor FLI1 is upregulated in many cancers, such as leukemias and lymphomas, and its genetic fusions with a gene coding for EWS protein cause Ewing sarcoma, a cancer of bone and soft tissue. The DNA binding domain of FLI1 is very similar to that of another transcription factor, ERG, whose genetic fusion with TMPRSS2 transforms prostate cancer cells into very aggressive forms. Depicted here is a crystal structure of the DNA binding domain of FLI1 in complex with DNA (see the manuscript below for more detail).
Hou, C. and Tsodikov, O.V. (2015) Structural basis for DNA binding and dimerization of transcription factor FLI1. Biochemistry., 54, 7365-7364.
Structural Basis of Drug Resistance in Tuberculosis
In the course of evolution, Mycobacterium tuberculosis has developed efficient mechanisms of inactivating drugs that would kill most other bacteria. As a consequence, many drug-resistant tuberculosis infections are very difficult to defeat, and limited or no therapeutic options can be offered to the patients. In collaboration with Dr. Sylvie Garneau-Tsodikova at the University of Kentucky, we are working on unraveling the elaborate mechanisms of drug resistance of tuberculosis.
Mycobacterium tuberculosis acetyltransferase Eis, responsible for
resistance to the drug kanamycin in many clinical isolates.
Chen, W., Biswas, T. et al. (2011) Proc. Natl. Acad. Sci. USA, 108, 9804-9808.
Our group is developing analytical tools with the ultimate goal of simplifying determination of macromolecular crystal structures from diffraction data.
Funding: These research programs are funded by the University of Kentucky College of Pharmacy, the National Institutes of Health and the US Department of Defense. We are greatful to these organizations for their support.