Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta.
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 alpha and beta 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 alpha and ER beta ligand complexes suggests that the biological effects of ER agonists and antagonists acting through these receptors are likely to be different.
Paige
L A
LA
Novalon Pharmaceutical Corporation, 4222 Emperor Boulevard, Suite 560, Durham, NC 27703, USA.
Christensen
D J
DJ
Grøn
H
H
Norris
J D
JD
Gottlin
E B
EB
Padilla
K M
KM
Chang
C Y
CY
Ballas
L M
LM
Hamilton
P T
PT
McDonnell
D P
DP
Fowlkes
D M
DM
D000595:Amino Acid Sequence; D001665:Binding Sites; D004958:Estradiol / Q000494:pharmacology; D045166:Estradiol Congeners / Q000494:pharmacology*; D004964:Estriol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation / Q000187:drug effects; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000187:drug effects; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
D045166:Estradiol Congeners; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D004964:Estriol