STRUCTURAL BASIS OF CELLULAR SIGNALING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We are proposing cutting-edge structural studies that are broadly relevant to vascular biology and immune deficiency. We will pursue crystallographic investigations on prostacyclin (PS) and thromboxane synthases (TS) to better understand how vasodilator and vasoconstrictor biosynthesis is mediated in vascular endothelial cells. This study is also important for gaining a better understanding of how drugs like Vioxx¿ and Celebrex¿ diminish prostacyclin production. Furthermore PS is a target for minoxidil ? the active ingredient of Rogaine¿. We also plan to combine the structural information obtained from our studies on PS and TS with allene oxide synthase (AOS) to provide a holistic view of how heme proteins utilize endo- and hydroperoxide substrates. Furthermore, by interrogating the structure of CYP8B1 ?sterol 12alpha hydroxylase? we will be able to provide a molecular basis for how novel functions evolve from preexisting cytochromes P450 templates and also gain insights into gallstone formation. On the immunodeficiency front we will determine the structure of activation-induced deaminase (AID), its complexes with DNA and other proteins. We will also probe chemokine receptors that belong to the G-protein couple receptor superfamily.