Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta

Estrogen receptor (ER) modulators produce distinct tissue-specific biologic al effects, but within the confines of the established models of ER action it is difficult to understand why. Previous studies have suggested that the re might be a relationship between ER structure and activity. Different ER modulators may induce conformational changes in the receptor that result in a specific biological activity. To investigate the possibility of modulato r-specific conformational changes, we have applied affinity selection of pe ptides to identify binding surfaces that are exposed on the apo-ERs alpha a nd beta and on each receptor complexed with estradiol or 4-OH tamoxifen. Th ese peptides are sensitive probes of receptor conformation. We show here th at ER ligands, known to produce distinct biological effects, induce distinc t conformational changes in the receptors, providing a strong correlation b etween ER conformation and biological activity, Furthermore, the ability of some of the peptides to discriminate between different ER alpha and ER bet a ligand complexes suggests that the biological effects of ER agonists and antagonists acting through these receptors are likely to be different.