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Publication Abstract from PubMed

Human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the last step in estrogen activation and is thus involved in estrogen-dependent diseases (EDDs). Unlike other 17beta-HSD members, 17beta-HSD1 undergoes a significant substrate-induced inhibition that we have previously reported. Here we solved the binary and ternary crystal structures of 17beta-HSD1 in complex with estrone and cofactor analog NADP(+) , demonstrating critical enzyme-substrate-cofactor interactions. These complexes revealed a reversely bound estrone in 17beta-HSD1 that provides the basis of the substrate inhibition, never demonstrated in estradiol complexes. Structural analysis showed that His(221) is the key residue responsible for the reorganization and stabilization of the reversely bound estrone, leading to the formation of a dead-end complex, which exists widely in NADP(H)-preferred enzymes for the regulation of their enzymatic activity. Further, a new inhibitor is proposed that may inhibit 17beta-HSD1 through the formation of a dead-end complex. This finding indicates a simple mechanism of enzyme regulation in the physiological background and introduces a pioneer inhibitor of 17beta-HSD1 based on the dead-end inhibition model for efficiently targeting EDDs. This article is protected by copyright. All rights reserved.

Crystal structures of human 17beta-hydroxysteroid dehydrogenase type 1 complexed with estrone and NADP(+) reveal the mechanism of substrate inhibition.,Li T, Stephen P, Zhu DW, Shi R, Lin SX FEBS J. 2019 Feb 15. doi: 10.1111/febs.14784. PMID:30768851^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.