6MNE

Crystal structures of human 17 beta-hydroxysteroid dehydrogenase type 1 complexed with estrone and NADP+reveal the mechanism of substrate inhibition.

(2019) FEBS J 286: 2155-2166

• PubMed: 30768851 Search on PubMed
• 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.

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Organizational Affiliation: 

Axe Molecular Endocrinology and Nephrology, CHU de Québec Research Center, Department of Molecular Medicine, Laval University, Québec, Canada.