CYP17A1 STRUCTURE FUNCTION, CRITICAL ENZYME IN HUMAN ANDROGEN BIOSYNTHESIS

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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. Prostate cancer is the most common occurring cancer and the second-leading cause of cancer-related death for men in the United States. Progression is strongly linked to the presence of androgens. Traditional androgen deprivation therapy significantly decreases androgen production in prostate tissue, but fails to inhibit adrenal androgen synthesis, leaving a basal level of androgens in circulation. Cytochrome P450 17A1 (CYP17A1) is responsible for the conversion of pregnenolone to androgens in both tissues. Thus, inhibition of CYP17A1 provides a strategy for complete deprivation of androgens in the treatment of prostate cancer. Several CYP17A1 inhibitors are currently in clinical trials, but there is currently no structural information about CYP17A1. The lack of a CYP17A1 crystal structure prevents an understanding of how current inhibitors work and how they might be improved. The objective of this proposal is to determine a structure of CYP17A1. Understanding the interaction between CYP17A1 and its ligands would provide information about how this enzyme functions. Our central hypothesis is that a crystal structure of CYP17A1 will reveal specific interactions that correspond to unique features of the enzyme. The specific aims are: 1) to engineer a soluble version of CYP17A1, 2) to optimize expression and purification strategies to generate mg quantities of pure, stable, functionally active, monodisperse CYP17A1 suitable for crystallization efforts, and 3) to grow diffraction-quality crystals of CYP17A1. The expected outcome of the proposed study is the first crystal structure of the important steroid biosynthetic enzyme CYP17A1. This structure will enable a detailed understanding of ligand binding modes.