Structural studies on a fungal 17beta-hydroxysteroid dehydrogenase: a model system for a human enzyme



Structural studies on a fungal 17β-hydroxysteroid dehydrogenase: a model system for a human enzyme


A. Cassetta, D. Lamba


PM.P06: Enabling technologies for drug discovery
PM.P06.001: Crystallography of biomolecules and functional studies


Hydroxysteroid dehydrogenases, Short Chain Dehydrogenase, Flavonoids, Breast Cancer

Faculty of Medicine, University of Ljubljana (Slovenja); Sincrotrone Trieste S. C. p. A, Trieste (Italy)

Steroid hormones act via specific receptors which activate gene transcription. 17β-Hydroxysteroid dehydrogenases (17β-HSDs) are responsible for pre-receptor regulation of estrogen or androgen steroid hormones action, by reducing, at position 17 the weakly active keto-form into the highly potent hydroxy-form or vice versa.

17β-HSDs are present in all vertebrates but even in primitive organism such as bacteria, yeasts and fungi. Several 17β-HSD human types have been related to the development of pathologies such as breast and prostate cancers, Alzheimer 's disease, polycystic kidney disease.
Part of the estrogens produced in women breast tissue are locally synthesized starting from precursors produced in different tissues. This specific estrogen synthetic pathway (Intracrine System) in post-menopausal women amounts for almost 100% of the total estrogens present in breast tissue. In hormone-dependent forms of breast cancer, the development of tumoral cells has been linked to the 17β-estradiol (E2) hormone level, mostly coming from the Intracrine way. The action of the Type 1 form of human 17β-HSD (17βHSD1) along the intracrine pathway is therefore essential in establishing high concentration of E2 in breast tissues.
We have undertaken a crystallographic study on a 17βHSD from the filamentous fungus Cochliobolus Lunatus, which shares functional and structural similarities with the human hortologues. Crystal structures of apo and holo enzyme have been obtained from crystallographic analysis for this enzyme. Moreover, we determined the crystallographic structure of ternary complexes with natural flavonoid inhibitors, which also inhibit 17βHSD1. The whole body of structural information, besides shedding light on the mechanism of action of the fungal enzyme, is important in gaining information on the mechanism of interactions of flavonoid-like molecular moieties with HSDs and could be important for the development of new synthetic inhibitors of 17βHSD1.


Structural studies on a fungal 17β-hydroxysteroid dehydrogenase:  a model system for a human enzyme - Img

Cassetta A, Büdefeld T, Lanisnik-Rizner TL, Kristan K, Stojan J, Lamba D. Crystallization, X-ray diffraction analysis and phasing of 17β-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus. Acta Cryst (2005) F61, 1032.



Alberto Cassetta
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Last Updated (Tuesday, 07 December 2010 11:33)