title: The ligand binding profiles of estrogen receptors alpha and beta are species dependent.
abstract: Estrogens and selective estrogen receptor modulators are used for the treatment and prevention of conditions resulting from menopause. Since estrogens exert their activity by binding to nuclear receptors, there is intense interest in developing new ligands for the two known estrogen receptor subtypes, ER-alpha and ER-beta. Characterization assays used to profile new estrogen receptor ligands often utilize receptors from different species, with the assumption that they behave identically. To test this belief, we have profiled a number of estrogens, other steroids, phytoestrogens and selective estrogen receptor modulators in a solid phase radioligand binding assay using recombinant protein for human, rat, and mouse ER-alpha and ER-beta. Certain compounds show species dependent binding preferences for ER-alpha or ER-beta, leading to differences in receptor subtype selectivity. The amino acids identified by crystallography as lining the ligand binding cavity are the same among the three species, suggesting that as yet unidentified amino acids contribute to the structure of the binding site. We conclude from this analysis that the ability of a compound to selectively bind to a particular ER subtype can be species dependent.
authors.affiliation: Women's Health Research Institute, Wyeth-Ayerst Research, 500 Arcola Road, Radnor, PA 19087, USA. harrish@war.wyeth.com
authors.forename: Heather A
authors.initials: HA
authors.lastname: Harris
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Bapat
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Gonder
authors.forename: Donald E
authors.initials: DE
authors.lastname: Frail
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D003001:Cloning, Molecular; D004958:Estradiol / Q000378:metabolism*; D020847:Estrogen Receptor Modulators / Q000378:metabolism; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal / Q000378:metabolism; D006801:Humans; D007529:Isoflavones; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D048789:Phytoestrogens; D028321:Plant Preparations; D010944:Plants; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity
chemical_list: D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal; D007529:Isoflavones; D008024:Ligands; D010446:Peptide Fragments; D048789:Phytoestrogens; D028321:Plant Preparations; D011960:Receptors, Estrogen; D004958:Estradiol