Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor

Abstract

A number of studies have reported on the unusual pharmacological behavior of type I antiestrogens, such as tamoxifen. These agents display mixed agonist/antagonist activity in a dose-, cell-, and tissue-specific manner. Consequently, many efforts have been made to develop so-called 'pure' antiestrogens that lack mixed agonist/antagonist activity. The recent report of the structure of estrogen receptor (ER) b with a second molecule of 4-hydroxytamoxifen (HT) bound in the coactivator-binding surface of the ligand-binding domain (LBD) represents the first direct example of a second ER ligand-binding site and provides insight into the possible origin of mixed agonist/antagonist activity of type I antiestrogens. In this review, we summarize the biological reports leading up to the structural conformation of a second ER ligand-binding site, compare the ERb LBD structure bound with two HT molecules to other ER structures, and discuss the potential for small molecular inhibitors designed to directly inhibit ER-coactivator and, more generally, nuclear receptor (NR)-coactivator interactions. The studies support a departure from the traditional paradigm of drug targeting to the ligand-binding site, to that of a rational approach targeting a functionally important surface, namely the NR coactivator-binding (activation function-2) surface. Furthermore, we provide evidence supporting a reevaluation of the strict interpretation of the agonist/antagonist state with respect to the position of helix 12 in the NR LBD.

A 155-plex high-throughput in vitro coregulator binding assay for (anti-)estrogenicity testing evaluated with 23 reference compounds

“…The binding profiles of these SeRMs are thus unique, as they are almost opposite to the profiles obtained with the known ER agonists and different from the profiles obtained with the negative controls and DMSO solvent control, indicating that the antagonistic properties of these SERMs mainly result from blocking the interaction of ERα with coactivator peptides rather than recruitment of corepressors. These findings are in agreement with other studies, showing that tamoxifen and 4-hydroxytamoxifen bind to the ligand-binding domain of ERα and cause a conformational shift of helix 12 into an adjacent coactivator site, which in turn prevents ERα from binding a coactivator (Shiau et al, 1998;Klinge et al, 2001;Pike et al, 1999;Konge et al, 2005;Kojetin et al, 2008). Moreover, the calculated IC50 values, based on all the coregulators showing a very good fit of the standard dose-response model, were 2.55×10 -7 M and 1.82×10 -9 M for tamoxifen and 4-hydroxytamoxifen, respectively.…”

Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

“…Several selective nuclear receptor modulators have been developed that directly inhibit the binding interaction between receptors and coactivators without affecting ligand binding. Examples include pyrimidines for ER␣ (60,61), hydroxytamoxifen for ER␤ (62,63), ketoconazoles for PXR (64,65), and ␤-aminoketones for TR (30,32,34). However, these inhibitors exhibit either poor potency in cellular models or intolerable toxicity in vivo.…”

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…However, the ERs have longer N-terminal (A/B domain; contains the AF-1 region) and C-terminal (F domain) domains. The F domain in particular appears to have an effect on the function of ER ligands, though the exact molecular mechanisms are not well understood (Kojetin et al, 2008;Skafar and Zhao, 2008). In addition, ER splice variants have been shown to influence the pharmacology of synthetic ER compounds, and site-specific phosphorylation of ER has been shown to modulate the gene-specific transcriptional response (Taylor et al, 2010;Duplessis et al, 2011).…”