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Signaling and Regulation

Flavone and Isoflavone Phytoestrogens Are Agonists of Estrogen-Related Receptors¹

¹ Department of Surgical Research and ² Division of Information Sciences, Beckman Research Institute of the City of Hope, Duarte, CA

Requests for reprints: Shiuan Chen, Department of Surgical Research, Beckman Research Institute of the City of Hope, 1450 East Duarte Road, Duarte, CA 91010. Phone: (626) 359-8111, ext. 63454; Fax: (626) 301-8972. E-mail: schen{at}coh.org

While estrogen-related receptors (ERR, ERRß, and ERR) share a high amino acid sequence homology with estrogen receptors (ERs), estrogens are not ligands of ERRs. Structure-function studies from this and other laboratories have revealed that ERRs have small ligand-binding pockets and have provided evidence to show that these receptors can activate gene transcription in a constitutive manner. To address the question as to whether there is any agonist for ERRs, our laboratory recently performed virtual ligand screening on ERR that predicted flavone and isoflavone phytoestrogens to be ligands of this receptor. Our mammalian cell transfection and mammalian two-hybrid experiments revealed that three isoflavones (genistein, daidzein, and biochanin A) and one flavone (6,3',4'-trihydroxyflavone) behaved as agonists of ERRs. These phytoestrogens induced the activity of ERR at concentrations that are comparable to those for the activation of ER and ERß. In this study, we also used the results of ERR ligand-binding site mutant, F232A, to verify our ERR hypothetical computer model. Our recent ERR research has determined for the first time that flavone and isoflavone phytoestrogens are agonists of ERRs. In addition, our studies have demonstrated that an approach that combines structure-based virtual screening and receptor functional assays can identify novel ligands of orphan nuclear receptors.

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