title: Mapping of steroids binding to 17 beta-hydroxysteroid dehydrogenase type 1 using Monte Carlo energy minimization reveals alternative binding modes.
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.
authors.affiliation: CHUL Research Centre, Laval University, Quebec City, Quebec, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Blanchet
authors.forename: Sheng-Xiang
authors.initials: SX
authors.lastname: Lin
authors.forename: Boris S
authors.initials: BS
authors.lastname: Zhorov
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000737:chemistry* / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D013196:Dihydrotestosterone / Q000737:chemistry / Q000378:metabolism*; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D010449:Peptide Mapping / Q000379:methods; D012984:Software; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D008024:Ligands; D013196:Dihydrotestosterone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase