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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor.

Authors: Kojetin, Douglas J; Burris, Thomas P; Jensen, Elwood V; Khan, Sohaib A

Published In Endocr Relat Cancer, (2008 Dec)

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) beta 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 ERbeta 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.

PubMed ID: 18755852 Exiting the NIEHS site

MeSH Terms: Amino Acid Sequence; Antineoplastic Agents, Hormonal/metabolism*; Binding Sites; Histone Acetyltransferases/metabolism; Humans; Molecular Sequence Data; Protein Binding; Receptors, Estrogen/chemistry; Receptors, Estrogen/metabolism*; Sequence Homology, Amino Acid; Tamoxifen/metabolism*; Trans-Activators/metabolism*; Transcription Factors/metabolism

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