'To develop compounds that are antagonists on ER(alpha), but not ER(beta), we have added basic side-chains typically found in nonsteroidal antiestrogens to pyrazole compounds that bind with much higher affinity to ER(alpha) than to ER(beta). In this way we have developed basic side-chain pyrazoles (BSC-pyrazoles) that are high affinity, potent, ... More
Hierarchical affinities and a bipartite interaction model for estrogen receptor isoforms and full-length steroid receptor coactivator (SRC/p160) family members.
AuthorsCheskis BJ, McKenna NJ, Wong CW, Wong J, Komm B, Lyttle CR, O'Malley BW,
JournalJ Biol Chem
PubMed ID12540843
Nuclear receptor (NR)-mediated transcription is driven by dynamic multiprotein coactivator complexes, the composition of which is thought to determine the biological activity of NRs at specific promoters. The extent to which NRs discriminate between a spectrum of potential binding partners is intuitively a function of the inherent affinities of these ... More
Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta.
Estrogen receptor (ER) modulators produce distinct tissue-specific biological effects, but within the confines of the established models of ER action it is difficult to understand why. Previous studies have suggested that there might be a relationship between ER structure and activity. Different ER modulators may induce conformational changes in the ... More
The effects of estrogen-responsive element- and ligand-induced structural changes on the recruitment of cofactors and transcriptional responses by ER alpha and ER beta.
Estrogen signaling is mediated by ER alpha and -beta. ERs are converted from an inactive form to a transcriptionally active state through conformational changes induced by ligand and estrogen-responsive element (ERE) sequences. We show here that ER alpha and ER beta bind to an ERE independently from ER ligands. We ... More
ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis.
Estrogens can regulate germ cell function. Estrogen action is mediated via high affinity ERs; two subtypes (ERalpha and ERbeta) have been identified. We have shown previously that ERbeta is expressed in nuclei of multiple human testicular cells. A variant isoform of human (h) ERbeta (hERbetacx/2), formed by alternative splicing, has ... More
Differential response of estrogen receptors alpha and beta to SP500263, a novel potent selective estrogen receptor modulator.
AuthorsBrady H, Doubleday M, Gayo-Fung LM, Hickman M, Khammungkhune S, Kois A, Lipps S, Pierce S, Richard N, Shevlin G, Sutherland MK, Anderson DW, Bhagwat SS, Stein B,
JournalMol Pharmacol
PubMed ID11854436
We determined the differential response of a novel SERM, SP500263, on estrogen receptor (ER) alpha and the more recently cloned ER-beta. Because of the high homology of amino acid residues in the ligand-binding domain of ER-alpha and ER-beta, we were not surprised to find that SP500263 binds to both ERs ... More
Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor alpha (ERalpha) and ERbeta in human cells.
AuthorsMueller SO, Simon S, Chae K, Metzler M, Korach KS,
JournalToxicol Sci
PubMed ID15084758
Phytoestrogens exert pleiotropic effects on cellular signaling and show some beneficial effects on estrogen-dependent diseases. However, due to activation/inhibition of the estrogen receptors ERalpha or ERbeta, these compounds may induce or inhibit estrogen action and, therefore, have the potential to disrupt estrogen signaling. We performed a comprehensive analysis and potency ... More