Estrogen and androgen discrimination by human 17beta-hydroxysteroid dehydrogenase type 1 and a conserved cofactor binding mode in the short-chain dehydrogenase/reductase family.

摘要

Human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD1), a member of the short-chain dehydrogenase/reductase (SDR) family, is responsible for the last step in the biosynthesis of all active estrogens. To understand the mechanism for steroid discrimination, we determined the structures of 17beta-HSD1 complexes with various C19-steroids (testosterone, androstanedione, androstenedione and dehydroepiandrosterone) using X-ray crystallography. All these complexes reveal that the C19-steroids bind in a reverse mode to 17beta-HSD1, which can be explained by the steric hindrance provided by the sandwich-like structure of Leu149/Val225 in the steroid binding site. Structure comparisons of all the estrogen-specific proteins demonstrated a common steroid-binding pocket architecture shared by these proteins to discriminate estrogens from androgens. Furthermore, the ternary complexes of 17beta-HSD1-NADP-C19-steroids, together with all available NAD(P)(H) complexes of different SDR proteins, demonstrate that the highly conserved hydrogen bonding interaction between the protein main-chain and the carboxamide group of NAD(P)(H) plays an important role in anchoring the nicotinamide ring to the SDR proteins.