Molecular basis of agonism and antagonism in the oestrogen receptor

@article{Brzozowski1997MolecularBO,
  title={Molecular basis of agonism and antagonism in the oestrogen receptor},
  author={Andrzej Marek Brzozowski and A C Pike and Zbigniew Dauter and Roderick E. Hubbard and Tomas Bonn and Owe Engström and Lars-Olof {\"O}hman and Geoffrey L. Greene and Jan-{\AA}ke Gustafsson and Mats Carlquist},
  journal={Nature},
  year={1997},
  volume={389},
  pages={753-758}
}
Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular… Expand
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References

SHOWING 1-10 OF 29 REFERENCES
Analysis of estrogen receptor transcriptional enhancement by a nuclear hormone receptor coactivator.
TLDR
It is demonstrated that SRC-1, which has been shown to significantly increase ER transcriptional activity, enhanced the interaction, mediated by either E2 or TOT, between the AF-1-containing and AF-2-containing regions of the ER. Expand
Antiestrogens: Mechanisms and actions in target cells
TLDR
In several cell systems, estrogens and protein kinase activators such as cAMP synergize to enhance the transcriptional activity of the ER in a promoter-specific manner and changes the agonist/antagonist balance of tamoxifen-like antiestrogens, increasing their agonistic activity and reducing their efficacy in reversing estrogen actions. Expand
Interaction of proteins with transcriptionally active estrogen receptors.
TLDR
Since the ability of these proteins to interact with the hormone binding domain correlates with its transcriptional activity, one or more of them may contribute to hormone-dependent transcriptional activation by the estrogen receptor. Expand
Tripartite steroid hormone receptor pharmacology: interaction with multiple effector sites as a basis for the cell- and promoter-specific action of these hormones.
TLDR
This commentary will examine the pharmacological mechanisms that underlie the selectivity of steroid hormone action and the development of new, synthetic hormones whose profile of desired activities is optimized for specific therapeutic and preventative applications. Expand
A canonical structure for the ligand-binding domain of nuclear receptors
TLDR
Mutant studies support a general mechanism for ligand-induced activation deduced from the comparison of the transcriptionally active RARγ holo- and inactive RXRα apo-LBD structures. Expand
Different Residues of the Human Estrogen Receptor Are Involved in the Recognition of Structurally Diverse Estrogens and Antiestrogens*
TLDR
This report compares the pattern of residues that are important in the recognition of several structurally diverse estrogen agonists and antagonists with those that are predicted to contact estradiol in the receptor-ligand complex and demonstrates that the smaller ligands have a narrower footprint of interacting residues than the larger ligands. Expand
Interaction of steroid hormone receptors with the transcription initiation complex.
TLDR
Interactions of the receptors with components of the basal transcriptional machinery and with sequence-specific transcription factors the authors show how steroid hormones modulate the activity of various genes in target cells through binding to intracellular receptors. Expand
Different Regions in Activation Function-1 of the Human Estrogen Receptor Required for Antiestrogen- and Estradiol-dependent Transcription Activation*
TLDR
It is found that estrogens and antiestrogen require different regions of AF-1 for transcriptional activation, and the agonist/antagonist balance and activity of antiestrogens such as TOT are determined by specific sequences within the A/B domain and thus may be influenced by differences in levels of specific factors that interact with these regions of the ER. Expand
The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer
TLDR
In addition to inducing the activation function associated with the HBD, estrogen plays a crucial role in the formation of stable ER dimers that bind tightly to ERE. Expand
Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors.
TLDR
It is proposed that the conserved region in the C‐terminus of the hormone binding domain between residues 538 and 552 in the mouse oestrogen receptor may be essential for ligand dependent transcriptional activation by other members of the nuclear receptor family. Expand
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