The long-range goal of this project is to study structure-function relationships in cytochromes P450 and related proteins using x-ray crystallography, molecular biology and biochemistry. Dr. Poulos has now solved three P450 structures; P450cam, the heme domain of the fatty acid hydroxylase P450BM-3 and P450eryF, an enzyme involved in the biosynthesis of the antibiotic erythromycin. The principal investigator has recently obtained crystals of P450BM-3 with a fatty acid substrate bound which should allow a comparison of three P450-substrate complexes in order to better understand those structural features that control substrate recognition, entry into the active site and specificity. Structures of the oxy and carbon monoxy complexes for all three will be determined at cryogenic temperatures. Various site directed mutants and inhibitor/drug complexes will be studied as well. New crystal structure work underway include heme oxygenase, an enzyme critical to heme homeostasis, and nitric oxide synthase.
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