Estrogen receptor beta (ER-beta) and estrogen-related receptor (ERR) (ER-beta/ERR)

The Estrogen receptor beta (ERβ, ESR2) and the Estrogen-related receptors (ERRα, ERRβ, ERRγ) are members of the NR3 class of the nuclear receptor superfamily (UniProt Q92731, P11474). ERβ is a ligand-activated transcription factor that binds 17β-estradiol and typically functions as a tumor suppressor, counteracting the proliferative signals of Estrogen receptor alpha in tissues like the breast and prostate (PubMed: 28438781). In contrast, the ERRs are orphan receptors that do not bind natural estrogens but are constitutively active or regulated by coactivators like PGC-1α to control mitochondrial biogenesis and energy metabolism (PubMed: 21664929). While ERβ is targeted by selective agonists for potential use in cancer and inflammatory diseases, ERRs are investigated for their roles in metabolic syndrome and heart failure (PubMed: 24014979). This grouping is pharmacologically complex because ERβ requires ligand binding for activation, whereas ERRs are primarily regulated by the availability of protein cofactors. Therapeutic development focuses on achieving high selectivity for ERβ over ERα to avoid feminizing side effects and on identifying synthetic inverse agonists for ERRs to treat metabolic disorders.

Other names

ESR2NR3A2ESRRAESRRBESRRGNR3B1NR3B2NR3B3ERR-alphaERR-betaERR-gamma

These receptors function as transcription factors that bind to specific DNA sequences, such as Estrogen Response Elements (EREs) or ERR Response Elements (ERREs), to regulate gene expression. ERβ undergoes a conformational change upon binding agonists, allowing it to recruit coactivators and initiate transcription (UniProt Q92731). ERRs, being orphan receptors, often rely on the recruitment of the PGC-1 family of coactivators to drive the expression of genes involved in oxidative phosphorylation and fatty acid oxidation (PubMed: 21664929).