Regulation of specific target genes and biological responses by estrogen receptor subtype agonists

Abstract

Estrogenic effects are mediated through two estrogen receptor (ER) subtypes, ERα and ERβ. Estrogens are the most commonly prescribed drugs to treat menopausal conditions, but by non-selectively triggering both ERα and ERβ pathways in different tissues they can cause serious adverse effects. The different sizes of the binding pockets and sequences of their activation function domains indicate that ERα and ERβ should have different specificities for ligands and biological responses that can be exploited for designing safer and more selective estrogens. ERα and ERβ regulate different genes by binding to different regulatory elements and recruiting different transcription and chromatin remodeling factors that are expressed in a cell-specific manner. ERα-selective and ERβ-selective agonists have been identified that demonstrate that the two ERs produce distinct biological effects. ERα and ERβ agonists are a promising new approach for treating specific conditions associated with menopause.

Figure 1

Comparison of the structures and homology between ERα and ERβ. Human ERα contains 595 amino acids whereas ERβ contains 530 amino acids. The DNA binding domains are nearly identical whereas the A/B domain and LBD, which contains AF-1 and AF-2, respectively, have the least homology.

Figure 2

Potential classes of estrogen receptor subtype agonists (ERSAs) for drug therapy. Potential ERβ-selective estrogens. (A) ERβ binders (ERB-041) are estrogens that are selective because they bind to ERβ with a much higher affinity than ERα. (B) ERβ activators (MF101, liquiritigenin) bind to ERα and ERβ with a similar affinity, but form a functional complex when bound to ERβ (left panel), but not ERα (right panel). An ERβ binder/activator (DPN) selectively binds to (A) and activates ERβ (B). Potential ERα-selective agonists. (C) ERα binders (PPT) bind to ERα with a much higher affinity than ERβ. (D) Tissue selective ERα agonists (Radix Glycyrrhiza and Radix Pueraria) form a functional transcription complex at response elements with ERα in some tissues (left panel), but not in other tissues (right panel). (E) A ligand such as E₂ binds to both ERα subunits that leads to the recruitment of coregulators and transcription factors (left panel). In the presence of an ERα coagonist (chalcone) E₂ binds to one subunit and the coagonist binds to the other subunit (right panel). The heteroliganded ERα could create a different conformation than the homoliganded ERα which leads to the recruitment of different coregulators and/or transcription factors.