Peptide Antagonists of the Human Estrogen Receptor

Abstract

Estrogen receptor alpha transcriptional activity is regulated by distinct conformational states that are the result of ligand binding. Phage display was used to identify peptides that interact specifically with either estradiol- or tamoxifen-activated estrogen receptor alpha. When these peptides were coexpressed with estrogen receptor alpha in cells, they functioned as ligand-specific antagonists, indicating that estradiol-agonist and tamoxifen-partial agonist activities do not occur by the same mechanism. The ability to regulate estrogen receptor alpha transcriptional activity by targeting sites outside of the ligand-binding pocket has implications for the development of estrogen receptor alpha antagonists for the treatment of tamoxifen-refractory breast cancers.

Problems for risk assessment of endocrine-active estrogenic compounds.

“…X-ray analysis of E 2 and SERMs bound to the ligand-binding domain of ERα and ERβ confirms that different structural classes of estrogenic compounds modulate ER conformation (40)(41)(42). We have confirmed this by showing that interaction profiles of polypeptides with ligand-bound ERα and ERβ are highly variable and dependent on ligand structure (43)(44)(45)(46)(47)(48). Further confirmation of ligand structure-dependent activity of SERMs has been shown in studies with human HepG cells transfected with an E 2 -responsive pC3-luc construct (containing the human complement C3 promoter linked to a luciferase reporter gene) and wild-type hERα or variant forms with a deletion of the activation factor 1 (AF1) domain (ERα-AF2) or critical mutations in the AF2 domain (ERα-AF1) (49,50).…”

The vitamin D receptor interacts preferentially with DRIP205-like LxxLL motifs

“…In similar phage display screens of the estrogen receptor mentioned above, the investigators were successful in identifying peptides capable of antagonizing ERα versus ERβ-mediated transcription [12,13,28]. In this study, we were also interested in identifying LxxLL-containing peptides that could serve as tools for studying VDR-mediated gene transcription given their ability to compete with endogenous coactivator proteins and block VDR-mediated transcription.…”

Tools to evaluate estrogenic potency of dietary phytoestrogens:A consensus paper from the EU Thematic Network “Phytohealth” (QLKI-2002-2453)

“…This possibility has been used owing to directly link conformational changes to agonist/antagonist properties toward ERα and ERβ of compounds already known to bind ERs (Wijayaratne et al, 1999;Norris et al, 1999).…”