New Insights into Human 17β-Hydroxysteroid Dehydrogenase Type 14: First Crystal Structures in Complex with a Steroidal Ligand and with a Potent Nonsteroidal Inhibitor

J Med Chem. 2016 Jul 28;59(14):6961-7. doi: 10.1021/acs.jmedchem.6b00293. Epub 2016 Jul 12.

Abstract

17β-HSD14 is a SDR enzyme able to oxidize estradiol and 5-androstenediol using NAD(+). We determined the crystal structure of this human enzyme as the holo form and as ternary complexes with estrone and with the first potent, nonsteroidal inhibitor. The structures reveal a conical, rather large and lipophilic binding site and are the starting point for structure-based inhibitor design. The two natural variants (S205 and T205) were characterized and adopt a similar structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • 17-Hydroxysteroid Dehydrogenases / metabolism
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Steroids / chemistry
  • Steroids / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Ligands
  • Pyridines
  • Steroids
  • dihydroxyphenylpyridine methanone
  • 17-Hydroxysteroid Dehydrogenases
  • 3 (or 17)-beta-hydroxysteroid dehydrogenase