Structure-based Ligand Discovery

Infectious disease is still the number one cause of mortality in the world.  Because of extensive overusage of antibiotics during the past few decades, infectious bacteria have become resistant to antibiotics and are spreading rapidly throughout the world.  It is therefore important to search for new antibacterials directed toward new targets.  Histidine kinases, which are abandant in bacteria but not in mammals, are an attractive target for anti-infective intervention.  Some histidine kinases are essential components of virulence mechanisms of a wide variety of bacterial pathogens.  We have recently determined the three-dimensional structure of the catalytic domain of the E. coli histidine kinase EnvZ (1BXD) (Tanaka et al., 1998).  This structure provides an excellent opportunity to rationally design inhibitors for histidine kinases.  We are currently undertaking various NMR and biochemical studies on EnvZ in collaboration with Dr. M. Inouye at Robert Wood Johnson Medical School.  The goal of this collaborative research is to identify potent inhibitors for histidine kinases.

Tomomori, C., Tanaka, T., Dutta, R., Park, H., Saha, S.K., Zhu, Y., Ishima, R., Liu, D., Tong, K.I., Kurokawa, H., Qian, H., Inouye, M., and Ikura, M. (1999)  Solution Structure of the Homodimeric Core Domain of Escherichia coli Histidine Kinase EnvZ.  Nature Struct. Biol. 6, 729-734.

Tanaka, T., Saha, S.K., Tomomori, C., Ishima, R., Liu, D., Tong, K.I., Park, H., Dutta, R., Qin, L., Swindells, M.B., Yamazaki, T., Ono, A.M., Kainosho, M., Inouye, M. and Ikura, M. (1998)  NMR Structure of the Histidine Kinase Domain of the E. coli Osmosensor EnvZ.  Nature 396, 88-92.