An illustration of the structure of the estrogen receptor. The NH2 terminal consists of the A/B domains, the C domain forms the DNA-binding domain (DBD) while domains D/E/F constitute the ligand-binding domain (LBD). The AF-1 and AF-2 activation units are part of the DNA-binding and ligand-binding domains, respectively. The two ER subtypes, ERα and ERβ, are almost identical in the DNA-binding domain (~95% homology) but differ in the ligand-binding domain (about 60% homology). Differences in the ligand-binding domain are responsible in part for ligand-specificity, and the ratio of ERα and ERβ is a critical determinant of cellular response to endogenous estrogen and other ER agonists and antagonists.