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Crystal structures of human 17β‐hydroxysteroid dehydrogenase type 1 complexed with estrone and NADP + reveal the mechanism of substrate inhibition
Author(s) -
Li Tang,
Stephen Preyesh,
Zhu DaoWei,
Shi Rong,
Lin ShengXiang
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14784
Subject(s) - dehydrogenase , cofactor , enzyme , estrone , chemistry , 11β hydroxysteroid dehydrogenase type 1 , ternary complex , stereochemistry , substrate (aquarium) , hydroxysteroid dehydrogenase , biochemistry , biology , ecology , hormone
Human 17β‐hydroxysteroid dehydrogenase type 1 (17β‐ HSD 1) catalyses the last step in estrogen activation and is thus involved in estrogen‐dependent diseases ( EDD s). Unlike other 17β‐ HSD members, 17β‐ HSD 1 undergoes a significant substrate‐induced inhibition that we have previously reported. Here we solved the binary and ternary crystal structures of 17β‐ HSD 1 in complex with estrone (E1) and cofactor analog NADP + , demonstrating critical enzyme‐substrate‐cofactor interactions. These complexes revealed a reversely bound E1 in 17β‐ HSD 1 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‐ HSD 1 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‐ HSD 1 based on the dead‐end inhibition model for efficiently targeting EDD s. Databases Coordinates and structure factors of 17β‐ HSD 1‐E1 and 17β‐ HSD 1‐E1‐ NADP + have been deposited in the Protein Data Bank with accession code 6MNC and 6MNE respectively. Enzymes 17β‐hydroxysteroid dehydrogenase type 1 (17β‐ HSD 1) EC 1.1.1.62.