MOLECULAR MODELING 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 p rotein 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 s hown 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 acid s for binding interactions with agonists and antagonists. A leucine-ri ch region, common to most steroid-binding proteins, is in an optimum p osition for dimerization leading to DNA interaction. It is likely that ligand binding influences dimerization and DNA interaction by a confo rmational change in the receptor via the transcriptional activation re sidues. This model suggests that ligand binding may affect the hydroge n bonding pattern such that transpeptide signalling is initiated. The model accommodates steroidal estrogens and antiestrogens as well as th e non-steroidal partial antagonist, hydroxytamoxifen.