The differential positioning of the activating function 2 (AF-2) helix 12 in the ligand-binding domain by the bound ligand determines whether the ligand has an agonistic and antagonistic effect. In agonist-bound receptors, helix 12 is positioned adjacent to helices 3 and 5. Helices 3, 5, and 12 together form a binding surface for an NR box motif contained in coactivators with the canonical sequence LXXLL (where L represents leucine or isoleucine and X is any amino acid). Unliganded (apo) receptors or receptors bound to antagonist ligands turn helix 12 away from the LXXLL-binding surface that leads to preferential binding of a longer leucine-rich motif, LXXXIXXX(I/L), present on the corepressors NCoR1 or SMRT. In addition, some cofactors bind to ER through the terminals, the DNA-binding site or other binding sites. Thus, one compound can be an ER agonist in a tissue rich in coactivators but an ER antagonist in tissues rich in corepressors.