4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma

The estrogen-related receptors (ERR alpha, ERR beta, and ERR gamma) form a family of orphan nuclear receptors that share significant amino acid identi ty with the estrogen receptors, but for which physiologic roles remain larg ely unknown. By using a peptide sensor assay, we have identified the stilbe nes diethylstilbestrol (DES), tamoxifen (TAM), and 4-hydroxytamoxifen (4-OH T) as high-affinity ligands for ERR gamma. In direct binding assays, 4-OHT had a K-d value of 35 nM, and both DES and TAM displaced radiolabeled 4-OHT with K-i values of 870 nM. In cell-based assays, 4-OHT binding caused a di ssociation of the complex between ERR gamma, and the steroid receptor coact ivator-1, and led to an inhibition of the constitutive transcriptional acti vity of ERR gamma. ERR alpha did not bind 4-OHT, but replacing a single ami no acid predicted to be in the ERR alpha ligand-binding pocket with the cor responding ERR gamma residue allowed high-affinity 4-OHT binding. These res ults demonstrate the existence of high-affinity ligands for the ERR family of orphan receptors, and identify 4-OHT as a molecule that can regulate the transcriptional activity of ERR gamma.