Download MendeleyCrystal structures of human 17 beta-hydroxysteroid dehydrogenase type 1 complexed with estrone and NADP+reveal the mechanism of substrate inhibition.
Li, T., Stephen, P., Zhu, D.W., Shi, R., Lin, S.X.(2019) FEBS J 286: 2155-2166
- PubMed: 30768851
- DOI: https://doi.org/10.1111/febs.14784
- Primary Citation of Related Structures:
6MNC, 6MNE - PubMed Abstract:
Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step in estrogen activation and is thus involved in estrogen-dependent diseases (EDDs). Unlike other 17β-HSD members, 17β-HSD1 undergoes a significant substrate-induced inhibition that we have previously reported. Here we solved the binary and ternary crystal structures of 17β-HSD1 in complex with estrone (E1) and cofactor analog NADP + , demonstrating critical enzyme-substrate-cofactor interactions. These complexes revealed a reversely bound E1 in 17β-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 E1, 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 17β-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 17β-HSD1 based on the dead-end inhibition model for efficiently targeting EDDs. DATABASES: Coordinates and structure factors of 17β-HSD1-E1 and 17β-HSD1-E1-NADP + have been deposited in the Protein Data Bank with accession code 6MNC and 6MNE respectively. ENZYMES: 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) EC 1.1.1.62.
Organizational Affiliation:
Axe Molecular Endocrinology and Nephrology, CHU de Québec Research Center, Department of Molecular Medicine, Laval University, Québec, Canada.
