Structural Molecular Biology of Bacterial Signal Transduction
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This project is part of a larger program aimed at determining the structural molecular biology of signal transduction in the sensor/response regulator systems of bacteria, with a particular focus here on the pathogen S. aureus that is responsible for 10% of all hospital acquired infections.
Staphylococcus aureus is a bacterial pathogen that is responsible for a broad range of infections, and is the agent responsible for 10% of all hospital acquired infractions. Bacteria respond to environmental stimuli via sensor molecules known as histidine kinases that detect environmental signals via a sensor (PAS) domain and autophosphorylates. This event initiates the phosphotransfer that activates the response regulator (RR) that turns on or off the required genes to elicit the desired cellular response. The YycG histidine kinase is a conserved is essential for survival of several key pathogens, and is therefore an excellent target for the development of anti-microbials. We propose to characterize the intra- and inter-molecular interactions that could provide anti-microbial targets for blocking signal transduction between the YycG histidine kinase and its cognate RR (YycF). We will use small-angle solution scattering (usng X-rays and neutrons) to determine the molecular architecture of the entire cytoplasmic region of YycG (which includes three domains; HAMP, PAS, and autokinase) as well as the interaction of YycG with YycF. Of particular interest is the relationship between the PAS domain and the autokinase module, since the only available PAS domain/autokinase domain structure indicates that the PAS domain might regulate both autophosphorylation and the subsequent phosphotransfer reaction. This project complements ongoing work in our lab that is focused on the structural molecular biology of histidine kinase regulation and is part of a larger collaborative effort with Professors J. Mitchell Guss (USyd), Glenn King (UQ), and William Burkholder (Stanford).
Our work requires a multidisciplinary approach using molecular biology, biochemistry, and biophysical tools. We frequently will use x-ray and neutron scattering to complement high resolution crystallographic and NMR data to enable us to probe the solution conformations of proteins and the complexes they form in a wide variety of conditions.
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The opportunity ID for this research opportunity is: 174