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Structural differences between the hormone and antihormone estrogen receptor complexes bound to the hormone response
M Sabbah1, F Gouilleux, B Sola
1Unité de Recherches sur les Communications Hormonales, Institut National de la Santé et de la Recherche Médicale, U.33, Bicêtre, France.
Summary
Estrogen receptor (ER) can bind DNA even without a ligand. Antagonist ICI164,384 alters ER structure, affecting gene transcription without preventing DNA binding.
Area of Science:
- Molecular Endocrinology
- Gene Regulation
- Protein-DNA Interactions
Background:
- The estrogen receptor (ER) plays a crucial role in modulating gene transcription.
- Understanding the molecular mechanisms of ER transcriptional regulation is essential.
Purpose of the Study:
- To investigate the molecular mechanisms of estrogen receptor (ER) mediated transcription.
- To compare the structures of ER complexes with different ligands: estradiol, diethylstilbestrol (agonist), and ICI164,384 (antagonist).
Main Methods:
- Gel retardation assays to assess ER binding to DNA response elements.
- Comparison of receptor complex structures under various ligand conditions.
- Exchange experiments to evaluate structural reversibility.
Main Results:
- ER can bind to the estrogen response element (ERE) of the Xenopus vitellogenin A2 gene independently of hormone, agonist, or antagonist binding.
- Ligand binding is not strictly required for ER dimerization or specific DNA binding in vitro.
- The antagonist ICI164,384 induces a conformational change in the ER-DNA complex, altering its electrophoretic mobility.
- This conformational change is reversible.
Conclusions:
- Ligand binding to the ER is not an absolute prerequisite for DNA binding and dimerization.
- Antagonist ICI164,384 induces specific conformational changes in the ER ligand-binding domain.
- These conformational modifications may prevent downstream events necessary for gene transcription, despite allowing DNA binding.