Human type 10 17β-hydroxysteroid dehydrogenase: molecular modelling and substrate docking

Abstract

17β-hydroxysteroid dehydrogenases catalyze the oxidoreduction of hydroxy/oxo groups at position C17 of steroid hormones, thereby constituting a prereceptor control mechanism of hormone action. At present, 11 different mammalian 17β-hydroxysteroid dehydrogenases have been identified, catalyzing the cell- and steroid-specific activation and inactivation of estrogens and androgens. The human type 10 17β-hydroxysteroid dehydrogenase (17β-HSD-10) is a multifunctional mitochondrial enzyme that efficiently catalyzes the oxidative inactivation at C17 of androgens and estrogens. However, it also mediates oxidation of 3α-hydroxy groups of androgens, thereby reactivating androgen metabolites. Finally, it is involved in β-oxidation of fatty acids by catalyzing the L-hydroxyacyl CoA dehydrogenase reaction of the β-oxidation cycle. These features and expression profiles suggest a critical role of 17β-HSD-10 in neurodegenerative and steroid-dependent cancer forms. Since no three-dimensional structure of 17β-HSD-10 is available, homology modelling was carried out to understand the molecular basis of these substrate specificities. The structure obtained displays the properties of a one-domain, α/β fold enzyme of the SDR family. The active site is located within a large, hydrophobic cleft, which forms optimal contacts with the different steroid surfaces. The data provide explanations for the substrate specificities toward the various classes of sex steroid hormones. The model is suitable to explore substrate and inhibitor characteristics that may be used in the development of novel strategies in the treatment of degenerative or malignant diseases.