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. (1) Eukaryotic cytochromes P450 (P450s) are ubiquitous, integral membrane enzymes that catalyze the mono-oxygenation of a large number of both exogenous and endogenous compounds. These reactions include pathways for the purging of environmental toxins and carcinogens, the synthesis of sterols, steroids and prostanoids and, in some cases, the metabolic activation of chemical carcinogens. A large number of laboratories study microsomal P450s and will benefit greatly from a structural model. We propose 1) to continue crystallographic studies of mammalian P450s to higher resolution in order to further characterize the membrane |attachment surface, 2) to determine what changes occur in the structure of the protein when substrate binds and the complex is reduced, and 3) to extend the crystallization methodology to related microsomal P450s of pharmacological interest. The structures to be determined in these studies will address questions about the interaction of the protein with the membrane as well as substrate binding and recognition. In addition, these studies will yield significant new information regarding modes of membrane binding, and may help to advance the methodology behind the engineering of membrane proteins for structural studies.
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