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This Article Full Text Full Text (PDF) All Versions of this Article: ERC-07-0281v1 15/4/851    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kojetin, D. J Articles by Khan, S. A PubMed PubMed Citation Articles by Kojetin, D. J Articles by Khan, S. A

Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, Ohio 45267-0521, USA¹ Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808, USA

(Correspondence should be addressed to S A Khan; Email: sohaib.khan{at}uc.edu)

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) β 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 ERβ 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.