Nuclear receptor coregulators are molecules critical for modulating steroid-receptor-mediated transcription. Some corepressors of nuclear receptors are the nuclear receptor corepressor (NcoR), the silencing mediator of retinoid and thyroid hormone receptors (SMRT) and the repressor of ER activity (REA). Corepressors suppress or silence gene expression by methylation of DNA and by binding to methyl-CpG-binding proteins that recruit corepressor complexes and histone deacetylase. Histone methylation, catalyzed by histone methyltransferases and reversed by histone demethylases, also modulates nuclear hormone signaling. Coactivators such as steroid receptor coactivator-1 (SRC-1), SRC-2 and SRC-3 increase ER-mediated transcription by chromatin remodeling through histone acetyltransferase activity and recruitment of other coactivators, including CREB-binding protein (CBP) and p300/CBP-associated factor. Many coregulators are enzymes that modify proteins through several mechanisms, including acetylation, methylation, phosphorylation and chromatin remodeling at sites where ERs are attached. Receptor activation by 17β-estradiol (E 2) requires a conformational change in the ligand-binding domain that includes formation of a hydrophobic pocket and modification of the surface that facilitates interaction with coregulatory proteins that may either enhance or suppress ER-dependent transcriptional activity.
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