title: Involvement of a Hydrophobic Pocket and Helix 11 in Determining the Modes of Action of Prenylated Flavonoids and Isoflavonoids in the Human Estrogen Receptor.
abstract: Six prenylated (iso)flavonoids were purified from a licorice root extract and subjected to competition experiments with six commercially available (iso)flavonoids. The agonistic and antagonistic activities of these compounds towards both hERα (human estrogen receptor alpha) and hERβ were determined. Differences in the modes of action (agonist or antagonist) were observed for the various compounds tested. In general, each compound had the same mode of action towards both ERs. In silico modeling was performed in order to study the differences in estrogenicity observed between the compounds. It is suggested that prenyl chains fit into a hydrophobic pocket present in the hER, resulting in an increased agonistic activity. In addition, it was shown that an increase in length (≈1.7 Å) of pyran prenylated isoflavonoids resulted in an antagonistic mode of action. This might be caused by collision of the pyran ring with helix 11 in the ligand binding cavity of the hER.
authors.affiliation: Laboratory of Food Chemistry, Wageningen University, P. O. Box 17, 6700 AA, Wageningen, The Netherlands.
authors.forename: Milou G M
authors.initials: MG
authors.lastname: van de Schans
authors.affiliation: Computational Discovery and Design Group, Center for Molecular and Biomolecular Informatics, Radboudumc, P. O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Tina
authors.initials: T
authors.lastname: Ritschel
authors.affiliation: Business Unit of Toxicology and Bioassays, RIKILT-Institute of Food Safety, P. O. Box 230, 6700 AE, Wageningen, The Netherlands.
authors.forename: Toine F H
authors.initials: TF
authors.lastname: Bovee
authors.affiliation: Laboratory of Food Chemistry, Wageningen University, P. O. Box 17, 6700 AA, Wageningen, The Netherlands.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Sanders
authors.affiliation: Wageningen NMR Centre, Wageningen University, P. O. Box 8128, 6700 ET, Wageningen, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: de Waard
authors.affiliation: Laboratory of Food Chemistry, Wageningen University, P. O. Box 17, 6700 AA, Wageningen, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Gruppen
authors.affiliation: Laboratory of Food Chemistry, Wageningen University, P. O. Box 17, 6700 AA, Wageningen, The Netherlands. jean-paul.vincken@wur.nl.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vincken
mesh_terms: D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D004965:Estrogen Antagonists / Q000737:chemistry / Q000378:metabolism; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism; D044950:Flavanones / Q000737:chemistry / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D006035:Glycyrrhiza / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D018517:Plant Roots / Q000737:chemistry / Q000378:metabolism; D054876:Prenylation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
chemical_list: C119737:8-prenylnaringenin; D004965:Estrogen Antagonists; D004967:Estrogens; D044950:Flavanones; D005419:Flavonoids; D008024:Ligands; D011960:Receptors, Estrogen
keywords: liquid chromatography; molar extinction coefficients; molecular modeling; prenylated flavonoids; structure-activity relationships