4FJ0

Crystal structure of the ternary complex between a fungal 17beta-hydroxysteroid dehydrogenase (Holo form) and 3,7-dihydroxy flavone

Summary for 4FJ0

• Entry DOI: 10.2210/pdb4fj0/pdb
• Related: 3IS3 3ITD 3QWF 3QWH 3QWI 4FIZ 4FJ1 4FJ2
• Descriptor: 17beta-hydroxysteroid dehydrogenase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: short chain dehydrogenase/reductase, rossmann fold, oxidoreductase, nadp(h), oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Cochliobolus lunatus (Filamentous fungus)
• Total number of polymer chains: 4
• Total formula weight: 119724.82

Authors

Cassetta, A.,Lamba, D.,Krastanova, I. (deposition date: 2012-06-11, release date: 2013-07-03, Last modification date: 2023-09-13)

Primary citation

Cassetta, A.,Stojan, J.,Krastanova, I.,Kristan, K.,Brunskole Svegelj, M.,Lamba, D.,Rizner, T.L.
Structural basis for inhibition of 17 beta-hydroxysteroid dehydrogenases by phytoestrogens: The case of fungal 17 beta-HSDcl.
J. Steroid Biochem. Mol. Biol., 171:80-93, 2017

PubMed Abstract: Phytoestrogens are plant-derived compounds that functionally and structurally mimic mammalian estrogens. Phytoestrogens have broad inhibitory activities toward several steroidogenic enzymes, such as the 17β-hydroxysteroid dehydrogenases (17β-HSDs), which modulate the biological potency of androgens and estrogens in mammals. However, to date, no crystallographic data are available to explain phytoestrogens binding to mammalian 17β-HSDs. NADP(H)-dependent 17β-HSD from the filamentous fungus Cochliobolus lunatus (17β-HSDcl) has been the subject of extensive biochemical, kinetic and quantitative structure-activity relationship studies that have shown that the flavonols are the most potent inhibitors. In the present study, we investigated the structure-activity relationships of the ternary complexes between the holo form of 17β-HSDcl and the flavonols kaempferol and 3,7-dihydroxyflavone, in comparison with the isoflavones genistein and biochanin A. Crystallographic data are accompanied by kinetic analysis of the inhibition mechanisms for six flavonols (3-hydroxyflavone, 3,7-dihydroxyflavone, kaempferol, quercetin, fisetin, myricetin), one flavanone (naringenin), one flavone (luteolin), and two isoflavones (genistein, biochanin A). The kinetics analysis shows that the degree of hydroxylation of ring B significantly influences the overall inhibitory efficacy of the flavonols. A distinct binding mode defines the interactions between 17β-HSDcl and the flavones and isoflavones. Moreover, the complex with biochanin A reveals an unusual binding mode that appears to account for its greater inhibition of 17β-HSDcl with respect to genistein. Overall, these data provide a blueprint for identification of the distinct molecular determinants that underpin 17β-HSD inhibition by phytoestrogens.

PubMed: 28259640
DOI: 10.1016/j.jsbmb.2017.02.020

Experimental method

X-RAY DIFFRACTION (2.2 Å)