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. The two-component regulatory system PhoPQ plays a central role in resistance to antimicrobial peptides and bacterial virulence. The PhoQ periplasmic sensor domain is essential for the activation and repression of PhoQ's kinase activity through its ability to sense environmental cues. There is strong evidence that divalent cations (Ca++ and Mg++) repress activation of PhoPQ by binding to the periplasmic domain of PhoQ. This binding likely induces a conformational change that is believed to transmit through the bacterial membrane, repressing activity of the PhoQ kinase domain responsible for induction of PhoP and further downstream processes. We are interested in the molecular mechanism of signal sensing and are investigating the structure of the sensor domain under varied environmental conditions.