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Dissociation of 4-hydroxytamoxifen, but not estradiol or tamoxifen aziridine, from the estrogen receptor as the receptor binds estrogen response element DNA
Ist Teil von
The Journal of steroid biochemistry and molecular biology, 1996, Vol.57 (1), p.51-66
Ort / Verlag
Oxford: Elsevier Ltd
Erscheinungsjahr
1996
Quelle
Elsevier ScienceDirect Journals
Beschreibungen/Notizen
Estradiol-liganded estrogen receptor (E
2-ER) binds EREs with a stoichiometry of one E
2-ER dimer per estrogen response element (ERE). In contrast, although 4-hydroxytamoxifen (4-OHT)-liganded ER (4-OHT-ER) binds EREs with high affinity, its saturation ERE binding capacity is consistently half that of E
2-ER, giving an apparent stoichiometry of one 4-OHT-ER monomer per ERE. Here we show that one molecule of 4-OHT ligand dissociates from the ER dimer apparently during the process of binding to DNA. Under equilibrium conditions, the type I antiestrogen tamoxifen aziridine (TAz), covalently attached to ER (TAz-ER), binds a single ERE with high affinity (
K
d = 0.27 nM), comparable to that of E
2-ER and 4-OHT-ER. In contrast to 4-OHT-ER, the ERE binding stoichiometry of TAz-ER was identical to that of E
2-ER: one dimeric receptor per ERE. By measuring [
3H]ligand that was initially bound to ER, a significant loss of [
3H]4-OHT from ER was detected after ERE binding, whereas all [
3H]E
2 or [
3H]TAz remained ER-bound. These results confirm that one molecule of 4-OHT ligand dissociates from the ER dimer as a consequence of ERE binding. Binding of 4-OHT and TAz are likely to induce a conformation in ER dimers that alters their capacity for gene activation. Upon ER binding to DNA, this conformation reveals itself by allowing 4-OHT dissociation, and predictably would allow TAz dissociation were it not bound covalently.