The enzyme 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) has become an important drug target for breast cancer because it catalyzes the interconversion of estrone to the biologically more potent estradiol which also plays a crucial role in the etiology of breast cancer. Patients with an increased expression of the 17β-HSD1 gene have a significantly worse outcome than patients without. Inhibitors for 17β-HSD1 are therefore included in therapy development. Here we have studied binding of 17β-HSD1 to substrates and a number of inhibitors using NMR spectroscopy. Ligand observed NMR spectra show a strong pH dependence for the phytoestrogens luteolin and apigenin but not for the natural ligands estradiol and estrone. Moreover, NMR competition experiments show that the phytoestrogens do not replace the estrogens despite their similar inhibition levels in the in vitro assay. These results strongly support an additional 17β-HSD1 binding site for phytoestrogens which is neither the substrate nor the co-factor binding site. Docking experiments suggest the dimer interface as a possible location. An additional binding site for the phytoestrogens may open new opportunities for the design of inhibitors, not only for 17β-HSD1, but also for other family members of the short chain dehydrogenases.
|Journal of Steroid Biochemistry and Molecular Biology
|Number of pages
|Published - 11.2009
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)