Estrogen receptor (ER) modulators each induce distinct conformational changes in ER α and ER β

LA Paige, DJ Christensen, H Grøn… - Proceedings of the …, 1999 - National Acad Sciences
LA Paige, DJ Christensen, H Grøn, JD Norris, EB Gottlin, KM Padilla, C Chang, LM Ballas…
Proceedings of the National Academy of Sciences, 1999National Acad Sciences
Estrogen receptor (ER) modulators produce distinct tissue-specific biological effects, but
within the confines of the established models of ER action it is difficult to understand why.
Previous studies have suggested that there 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 modulator-specific
conformational changes, we have applied affinity selection of peptides to identify binding …
Estrogen receptor (ER) modulators produce distinct tissue-specific biological effects, but within the confines of the established models of ER action it is difficult to understand why. Previous studies have suggested that there 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 modulator-specific conformational changes, we have applied affinity selection of peptides to identify binding surfaces that are exposed on the apo-ERs α and β and on each receptor complexed with estradiol or 4-OH tamoxifen. These peptides are sensitive probes of receptor conformation. We show here that ER ligands, known to produce distinct biological effects, induce distinct conformational changes in the receptors, providing a strong correlation between ER conformation and biological activity. Furthermore, the ability of some of the peptides to discriminate between different ER α and ER β ligand complexes suggests that the biological effects of ER agonists and antagonists acting through these receptors are likely to be different.
National Acad Sciences