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  • Insights into subtle conformational differences in the substrate-binding loop of fungal 17ß-hydroxysteroid dehydrogenase : a combined structural and kinetic approach
    Cassetta, Alberto ...
    17beta-Hydroxysteroid dehydrogenase from the filamentous fungus Cochliobolus lunatus (17beta-HSDcl) is a NADP(H)-dependent enzyme that preferentially catalyzes the interconversion of inactive ... 17-keto-steroids and their active 17beta-hydroxy counterparts. 17beta-HSDcl belongs to the short-chain dehydrogenase/ reductase superfa mily (SDR). It is currently the only fungal HSD member that has been described and represents one of the model enzymes ofthe cP1 classical subfamily of NADPH dependent SDR enzymes. A thorough crystallographic analysis has been performed to better understand the structural aspects of this subfamily and provided insights into the evolution of the HSD enzymes. The crystal structures of the 17beta-HSDcl apo, holo and coumestrol-inhibited ternary complex, and the active site Y167F mutant reveal subtle conformational differences in the substrate-binding loop that likely modulate the catalytic activity of 17beta-HSDcl. Coumestrol, a plant-derived non-steroidal compound with estrogenic activity, inhibits 17beta-HSDcl (IC50, 2.8 mM; at 100 muM substrate š4-estrene-3,17-dioneđ) by occupying the putativesteroid-binding site. In addition to an extensive hydrogen-bonding network, coumestrol binding is further stabilized by pi-pi stacking interactions with Tyr-212. A stopped-flow kinetic experiment clearly showed the coenzyme dissociation as the slowest step of the reaction and in addition to the low steroid solubility it prevents the accumulation of enzyme-coenzyme-steroid ternary complex formation.
    Vir: Biochemical journal. - ISSN 0264-6021 (Vol. 441, part 1, 2012, str. 151-160)
    Vrsta gradiva - članek, sestavni del
    Leto - 2012
    Jezik - angleški
    COBISS.SI-ID - 28926169
    DOI
vir: Biochemical journal. - ISSN 0264-6021 (Vol. 441, part 1, 2012, str. 151-160)
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