| The estrogen receptor is a nuclear receptor transcription factor for which ligand binding mediates dissociation with heat shock proteins, dimerization, and modulation of transcription through either direct binding to DNA or interaction with other transcriptional proteins. The most carboxy-terminal helix, helix 12, of the ligand binding domain acts as a molecular switch, forming one side of a cofactor binding site in the presence of agonist ligands. In order to understand the structural connection between ligand and protein cofactors, ligands selective for one of the two estrogen receptor subtypes, alpha and beta, were compared. Three ligands were examined that act as agonists on ER alpha but antagonists on ER beta. The structural basis of this selectivity was detailed based on a structural analysis of all published crystal structures. In addition to amino acids in the ligand binding pocket, residues on the surface, hydrophobic core, and around helix 12 were identified as contributing to ligand selectivity, which varied by ligand. These data suggest an important role for long range communication in the estrogen receptor ligand binding domain. |
