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Michiels, P.J.* ; Ludwig, C.* ; Stephans, M.* ; Fischer, C.* ; Möller, G. ; Adamski, J. ; Messinger, J.* ; van Dongen, M.* ; Thole, H.* ; Günther, U.L.*

Ligand-based NMR spectra demonstrate an additional phytoestrogen binding site for 17β-hydroxysteroid dehydrogenase type 1.

J. Steroid Biochem. Mol. Biol. 117, 93-98 (2009)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
The enzyme 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) has become an important drug target for breast cancer because it catalyzes the interconversion of estrone to the biologically more potent estradiol which also plays a crucial role in the etiology of breast cancer. Patients with an increased expression of the 17beta-HSD1 gene have a significantly worse outcome than patients without. Inhibitors for 17beta-HSD1 are therefore included in therapy development. Here we have studied binding of 17beta-HSD1 to substrates and a number of inhibitors using NMR spectroscopy. Ligand observed NMR spectra show a strong pH dependence for the phytoestrogens luteolin and apigenin but not for the natural ligands estradiol and estrone. Moreover, NMR competition experiments show that the phytoestrogens do not replace the estrogens despite their similar inhibition levels in the in vitro assay. These results strongly support an additional 17beta-HSD1 binding site for phytoestrogens which is neither the substrate nor the co-factor binding site. Docking experiments suggest the dimer interface as a possible location. An additional binding site for the phytoestrogens may open new opportunities for the design of inhibitors, not only for 17beta-HSD1, but also for other family members of the short chain dehydrogenases.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 17β-hsd1 Nmr ; 17β-hydroxysteroid Dehydrogenase Type-1 ; Epitope Mapping ; Hydroxysteroid Dehydrogenase
ISSN (print) / ISBN 0960-0760
e-ISSN 0960-0760
Zeitschrift Journal of Steroid Biochemistry and Molecular Biology, The
Quellenangaben Band: 117, Heft: 4-5, Seiten: 93-98 Artikelnummer: , Supplement: ,
Verlag Elsevier
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Molekulare Endokrinologie und Metabolismus (MEM)