The structure of a complex of human 17β-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitors

Abstract

From the structure of the complex of the enzyme with the substrate and cofactor of the oxidation reaction, the orientation of the substrates for the reduction reaction can be deduced with confidence. A triangular hydrogen-bond network between Tyr155, Ser142 and O17 from estradiol probably facilitates the deprotonation of the reactive tyrosine, while the conserved Lys159 appears not to be directly involved in catalysis. Both the steroid-binding site and the NADPH-binding site can be proposed as targets for the design of inhibitors.

The role of the heterocycle in bis(hydroxyphenyl)triazoles for inhibition of 17β-Hydroxysteroid Dehydrogenase (17β-HSD) type 1 and type 2

“…Until now, several groups have reported on 17β-HSD1 inhibitors, most of them showing steroidal structures (for reviews see : Poirier, 2003;Brožic et al, 2008). Concerning the nonsteroidal cores, only four compound classes have been described so far: thienopyrimidinones Karkola et al, 2008), biphenyl ethanones (Allan et al, 2008), from our group 6-(hydroxyphenyl) naphthols and recently, we reported on bis(hydroxyphenyl)azoles as potent and selective inhibitors of 17β-HSD1.…”

“…The analysis of the available ternary complex of 17β-HSD1 with E2 and NADP + (PDB-ID: 1FDT; Breton et al, 1996) provided useful informations about the architecture of the active site of the enzyme. A substrate binding site and a cofactor binding pocket can be defined.…”

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

“…The surface of the tunnel is complementary to the C 18 steroidal scaffold and ensures selectivity towards estrogenic substrates 26 . At the C-terminal recognition end, hydrophilic amino acids form hydrogen-bonds to the 3-hydroxy group of the substrate 27,28 . These interactions fix the substrate and its C-17 oxo into an appropriate orientation for the catalytic transformation 7,24,29 , but they have been found not to be essential for the binding, and they may even establish a catalytically unfavourable position for noncognate substrates 30 .…”

Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme

“…Interestingly, some important structural differences can be observed when comparing for example the co-crystal of estradiol bound to h17β-HSD1 (PDB-ID: 1FDT) with that one of reported inhibitor E 2 B (PDB-ID 3HB5). [48,49] In the former complex, the side chain of Lys195 is oriented inwards and towards the active site, thereby occupying a notable volume of the inhibitor binding region (see Supporting Figure S1). On the other hand, in 3HB5 this side chain is oriented outside of the protein.…”