Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 26, Pages 9908-9911Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0510596103
Keywords
antiestrogen; crystallography; nuclear receptor
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Funding
- NCI NIH HHS [CA 72039, R01 CA072039] Funding Source: Medline
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Evidence is presented that the estrogen antagonist 4-hydroxytamoxifen (HT) can occupy not only the core binding pocket within the ligand-binding domain of estrogen receptor (ER) 13 but also a second site on its surface. The crystal structure of the ligand-binding domain (LBD) associated with HT was determined to 2.2 angstrom and revealed two molecules of HT bound to the protein. One was located in the consensus ligand-binding pocket, whereas the other bound to a site that overlaps with the hydrophobic groove of the coactivator recognition surface. Relative to the ER alpha-tamoxifen structure, helix 12 has been displaced from the coactivator recognition surface and occupies a unique position. Although it has been demonstrated that association of the antagonist with the core ligand-binding pocket is sufficient to induce an antagonist ligand-binding domain conformation, this structure suggests that small molecules may directly antagonize receptor-coactivator interactions. These results provide a direct demonstration of two binding sites for HT in ER beta, as has been previously suggested for ER alpha by using biochemical methods, and represent a crystal structure of a small nonpeptide molecule occupying the coactivator recognition site.
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