Molecular modelling of the human estrogen receptor and ligand interactions based on site-directed mutagenesis and amino acid sequence homology.

A molecular model of the human estrogen receptor is reported based on a new alignment with the alpha 1-antitrypsin sequence, a homologous protein of known crystal structure. The putative ligand binding site is situated roughly equidistant between the DNA binding and dimerization regions. This binding site contains a number of amino acid residues shown by site-directed mutagenesis to be associated with the binding of agonists and antagonists. This putative ligand binding pocket is well-defined within a loop of peptide, containing complementary amino acids for binding interactions with agonists and antagonists. A leucine-rich region, common to most steroid-binding proteins, is in an optimum position for dimerization leading to DNA interaction. It is likely that ligand binding influences dimerization and DNA interaction by a conformational change in the receptor via the transcriptional activation residues. This model suggests that ligand binding may affect the hydrogen bonding pattern such that transpeptide signalling is initiated. The model accommodates steroidal estrogens and antiestrogens as well as the non-steroidal partial antagonist, hydroxytamoxifen.