title: A second binding site for hydroxytamoxifen within the coactivator-binding groove of estrogen receptor beta.
abstract: 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) beta 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 A 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 ERalpha-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 ERbeta, as has been previously suggested for ERalpha by using biochemical methods, and represent a crystal structure of a small nonpeptide molecule occupying the coactivator recognition site.
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Nickolay Y
authors.initials: NY
authors.lastname: Chirgadze
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Briggs
authors.forename: Sohaib
authors.initials: S
authors.lastname: Khan
authors.forename: Elwood V
authors.initials: EV
authors.lastname: Jensen
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry*; D001665:Binding Sites; D003461:Crystallography; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047629:Estrogen Receptor beta; D013629:Tamoxifen; C016601:afimoxifene