This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Structural studies of bacterial signal-transduction protein complexes Histidine kinases have been attractive new targets for drug design to circumvent drug resistance in Gram-positive pathogenic bacteria. Our research is aimed at structures and functions of a multi-domainal, membrane-spanning histidine kinase and its response regulator from an essential two-component signal transduction system. Proposal: Histidine kinase of Gram-positive pathogenic bacteria Resistance to common antimicrobial drugs is a global phenomenon, and an increase in resistance has been observed for every major group of bacterial pathogens. There is an obvious need for identification of novel targets for development of new antimicrobials. Two-component systems are ubiquitous in bacteria and are central elements of the intricate regulatory pathways utilized by pathogenic bacteria to control a wide range of cellular processes including expression of virulence factors and resistance to certain antimicrobial. A paradigmatic two-component system consists of two proteins: sensor kinase and response regulator. The sensor kinases monitor environmental signals, and modulate functions of response regulators through phosphotransfer reactions. The response regulators usually contain an N-terminal receiver domain and a C-terminal DNA-binding domain. The receiver domain receives signals from histidine kinase through phosphorylation, which enables the DNA-binding domain to act as a transcription factor to regulate expression of certain genes. YycF (response regulator):YycG (histidine kinase) system is highly conserved in the low G+C Gram-positive bacteria including Bacillus subtilis, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes and Listeria monocytogenis, many of which are human pathogens and pose significant threat on public health in the U.S. and worldwide. The YycF:G system is the only two-component system essential for cell viability known to date, and has been suggested as a prime antimicrobial target and subjected to small-molecule inhibitor developments. The YycF:G system has been implied in cell wall biogenesis. However, it is not clear what signal YycG senses and how the signal is relayed in the YycF:G system.
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