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  • Title: Dissociation of 4-hydroxytamoxifen, but not estradiol or tamoxifen aziridine, from the estrogen receptor as the receptor binds estrogen response element DNA.
    Author: Klinge CM, Traish AM, Bambara RA, Hilf R.
    Journal: J Steroid Biochem Mol Biol; 1996 Jan; 57(1-2):51-66. PubMed ID: 8645617.
    Abstract:
    Estradiol-liganded estrogen receptor (E2-ER) binds EREs with a stoichiometry of one E2-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 E2-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 (Kd = 0.27 nM), comparable to that of E2-ER and 4-OHT-ER. In contrast to 4-OHT-ER, the ERE binding stoichiometry of TAz-ER was identical to that of E2-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]E2 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.
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