Structure and function of the estrogen receptor.

The hormone binding domain of the estrogen receptor is required not only for binding estradiol but also to form stable homodimers of the protein and mediate transcriptional activation by the receptor. Residues that are essential for estrogen binding are also involved in dimerization, suggesting that the hormone-binding pocket is at or near the dimer interface. Distinct hydrophobic and charged residues are essential for hormone-dependent transcriptional activation, and these appear to be conserved by other members of the nuclear receptor family. We have found that the pure antiestrogens ICI 164384 and ICI 182780 increase the turnover of the receptor compared with that in the presence of estradiol. Because it is likely that the pure antiestrogens bind to a similar region of the receptor as that of estradiol, we propose that they inhibit receptor dimerization by means of their 7 alpha alkyl-amide extension. It appears that as a consequence nuclear uptake is inhibited and the receptor more rapidly degraded in the cytoplasm.