X-ray crystallography of estrogens or antiestrogens has shown how ligands program the receptor complex to interact with other proteins. The ligand-binding domain of the ER demonstrates how ligands promote and prevent coactivator binding based on the shape of the estrogen or antiestrogen complex. The broad range of ligands that bind to the ER can create a spectrum of ER complexes that are fully estrogenic or antiestrogenic at a specific target site. The main result of a ligand-binding to ER is a structural rearrangement of the ligand-binding pocket, primarily in the AF-2 of the C-terminal region. The binding of ligands to ER leads to the formation of a hydrophobic pocket that regulates cofactors and receptor pharmacology. The correct folding of ligand-binding domain is required for activation of transcription and for ER to interact with a number of coactivators (see figure 4).