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Development of peptide antagonists that target estrogen receptor beta-coactivator interactions
J M Hall1, C Y Chang, D P McDonnell
1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract:
The biological actions of estrogen are manifest through two genetically distinct estrogen receptors (ER alpha and ER beta) that display nonidentical expression patterns in target tissues. The phenotypic alterations in response to estrogens in mice disrupted for either or both of these receptors are not identical, suggesting that each subtype plays a unique role in ER-action. However, the lack of subtype-specific agonists and antagonists has made it difficult to define the processes that are regulated by ER alpha and/or ER beta. Previously, we have reported the identification and characterization of a series of LXXLL-containing peptide antagonists that block estrogen signaling by preventing the association of ER alpha with required coactivators. As expected, given the similarity of the coactivator binding pockets among nuclear receptors, most of the peptide antagonists identified inhibited the activity of multiple receptors. However, by altering sequences flanking the core LXXLL motif, some receptor selectivity was afforded. Building on this observation, we have screened combinatorial phage libraries, expressing peptides in the format X7LXXLLX7, for peptides that interact in a specific manner with ER beta. Using this approach, a series of highly specific, potent peptide antagonists have been identified that efficiently inhibit ER beta-mediated estrogen signaling when introduced into target cells. Interestingly, in cells where both ER subtypes were expressed, these ER beta antagonists were capable of attenuating ER action, suggesting that ER alpha and ER beta do indeed form functional heterodimeric complexes. We believe that suitably formulated versions of these peptides can be used to study ER beta action in vitro and in vivo. In addition, the unanticipated specificity of the peptides identified should serve as an impetus to investigate the use of this approach to develop peptide antagonists of other nuclear receptors and unrelated transcription factors.
Insights
Researchers developed specific peptide antagonists targeting estrogen receptor beta (ER beta). These compounds effectively block ER beta activity and suggest ER alpha and ER beta form functional complexes, aiding future research.
Area of Science:
- Endocrinology
- Molecular Biology
- Pharmacology
Background:
- Estrogen exerts biological effects via two receptors: ER alpha and ER beta.
- These receptors have distinct expression patterns and roles in estrogen signaling.
- Lack of subtype-specific modulators hindered understanding of individual receptor functions.
Purpose of the Study:
- To identify and characterize specific antagonists for estrogen receptor beta (ER beta).
- To investigate the potential for functional heterodimerization between ER alpha and ER beta.
Main Methods:
- Screening of combinatorial phage libraries expressing X7LXXLLX7 peptides.
- Characterization of peptide antagonists for ER beta specificity and potency.
- Testing antagonist efficacy in cells expressing both ER alpha and ER beta.
Main Results:
- Identification of highly specific and potent peptide antagonists for ER beta.
- Demonstrated inhibition of ER beta-mediated estrogen signaling in target cells.
- Observed attenuation of overall estrogen action in cells co-expressing both ER subtypes, indicating functional heterodimers.
Conclusions:
- Developed specific peptide antagonists for ER beta, enabling detailed study of its actions.
- Provided evidence for functional heterodimeric complexes between ER alpha and ER beta.
- Highlighted the potential of this peptide-based approach for developing antagonists for other nuclear receptors.