Comparative Structural Analysis of Er-alpha and Er-beta Bound to Selective Estrogen Agonists and Antagonists

摘要

The goal of this investigation is to determine the three-dimensional structures of the two known human estrogen receptors (ER-alpha and ER-beta) complexed with receptor-selective estrogens and antiestrogens (SERMs). The crystallographic structures of ER-alpha and ER-beta ligand binding domains complexed with cis-R,R-diethyl-tetrah ydrochrysene-2,8-diol (R,R-THC) have been solved and refined, suggesting mechanisms by which this compound can act as an ER-alpha agonist and as an ER-beta antagonist. Agonists and antagonists bind at the same site within the core of the ER LBD to induce distinct conformations in the transactivation domain (AF-2), especially in the positioning of helix 12. Previously determined structures of ER-alpha with 4-hydroxytamoxifen (OHT) and diethylstilbestrol (DES) revealed and defined a multipurpose docking site on ER- alpha and ER-beta that can accommodate either helix 12, in the presence of OHT, or one of several co-regulators in the presence of DES. R,R-THC stabilizes a conformation of the ER-alpha LED that favors coactivator association and a conformation of the ER-alpha LBD that prevents coactivator association. A comparison of the two structures, combined with functional data, reveals that THC does not act on ER-beta through the same mechanisms used by other known ER antagonists. Instead, THC antagonizes ER-beta through a novel mechanism we term 'passive antagonism'. Paradoxically, the R,R-THC-ER-beta structure is very similar to the structure induced by genistein, which acts as a partial estrogen through both ER subtypes. Ongoing mutagenesis studies have helped define some of the molecular and structural differences that are responsible for these unanticipated results. The passive antagonism mechanism, combined with mutagenesis data, suggests a novel approach to the design of ligands that selectively antagonize the two ER subtypes. Such ligands may have therapeutic properties that can be exploited to prevent or treat breast cancer.