Publication: Mapping of steroids binding to 17 beta-hydroxysteroid dehydrogenase type 1 using Monte Carlo energy minimization reveals alternative binding modes
All || By Area || By Year| Title | Mapping of steroids binding to 17 beta-hydroxysteroid dehydrogenase type 1 using Monte Carlo energy minimization reveals alternative binding modes | Authors/Editors* | Blanchet J, Lin SX, Zhorov BS |
|---|---|
| Where published* | Biochemistry |
| How published* | Journal |
| Year* | 2005 |
| Volume | 44 |
| Number | 19 |
| Pages | 7218-27 |
| Publisher | |
| Keywords | |
| Link | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15882060&query_hl=1&itool=pubmed_docsum |
| Abstract |
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. |
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