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. Human steroid (Estrone/DHEA) sulfatase (STS) and cytochrome P450 aromatase (P450arom), two integral membrane proteins of the endoplasmic reticulum, catalyze biosynthesis of the active estrogens. Selective inhibition of one or more of these enzymes by high affinity, highly specific small molecule inhibitors could provide an effective means of prevention and treatment of hormone-dependent breast carcinoma. We have determined the crystal structure of full-length STS purified from human placenta at 2.1 angstrom resolution. In order to investigate molecular mechanisms of activation and inhibition of the enzyme, we continue to analyze the structures of its complexes with ligands and inhibitors. The plan is to gather X-ray diffraction data on newly grown crystals of inhibited complexes of STS. Recently, we have for the first time grown large single crystals of androstenedione-complex of the full-length P450arom, also purified from human placenta. With CHESS beam time, we plan to conduct cryo-protection optimization experiments and collect diffraction data for solving the crystal structure.
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