Mapping of steroids binding to 17 beta-hydroxysteroid dehydrogenase type 1 using Monte Carlo energy minimization reveals alternative binding modes

Biochemistry. 2005 May 17;44(19):7218-27. doi: 10.1021/bi047553x.


Crystallographic studies of ligand-protein complexes reveal most preferable ligand binding modes, but do not show less populated modes that may contribute to measurable biochemical and biophysical characteristics of the complexes. In some cases, a ligand may bind a protein in essentially different modes. An example is 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), a steroidogenic enzyme that catalyzes reduction of estrone to estradiol in gonadal and peripheral tissues. The enzyme exhibits a high specificity for estrogens which bind with their C17 atom in the proximity of the NADP(H) cofactor. 17Beta-HSD1 can also bind androgens, but in a reverse binding mode, in which the steroid C3 atom is the closest carbon atom to the cofactor. Here we map the interaction energy of estradiol and dihydrotestosterone binding to 17beta-HSD1. Positions and orientations of the steroids in the ligand-binding tunnel were sampled systematically, and at each combination of these generalized coordinates, the energy was Monte Carlo minimized. The computed maps show energy minima corresponding to the X-ray structures and predict alternative binding modes, in particular, an upside-down orientation in which steroidal face alpha is exposed to protein residues that normally interact with face beta. The methodology can be used for mapping ligand-receptor interactions in various systems, for example, in ion channels and G-protein-coupled receptors that bind elongated ligands in confined space between transmembrane helices.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases / chemistry*
  • 17-Hydroxysteroid Dehydrogenases / metabolism*
  • Amino Acid Sequence
  • Binding Sites
  • Computational Biology* / methods
  • Computer Simulation
  • Crystallography, X-Ray
  • Dihydrotestosterone / chemistry
  • Dihydrotestosterone / metabolism*
  • Estradiol / chemistry
  • Estradiol / metabolism*
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Monte Carlo Method*
  • Peptide Mapping / methods
  • Software
  • Substrate Specificity
  • Thermodynamics*


  • Ligands
  • Dihydrotestosterone
  • Estradiol
  • 17-Hydroxysteroid Dehydrogenases
  • 3 (or 17)-beta-hydroxysteroid dehydrogenase