Comparative Structural Analysis of ERa and ERb 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 (ERalpha and ERbeta) complexed with receptor-selective estrogens and antiestrogens (SERMs) The crystallographic structures of ERalpha and ERbeta 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 ERalpha agonist and as an ERbeta 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 ERa with 4-hydroxytamoxifen (OHT) and diethylstilbestrol (DES) revealed and defined a multipurpose docking site on ERalpha and ERbeta 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 ERalpha LBD that favors coactivator association and a conformation of the ERbeta LBD that prevents coactivator association. A comparison of the two structures, combined with functional data, reveals that THC does not act on ERbeta through the same mechanisms used by other known ER antagonists. Instead, THC antagonizes ERbeta through a novel mechanism we term 'passive antagonism'. Paradoxically, the R,R-THC-ERbeta structure is very similar to the structure induced by genistein, which acts as a partial estrogen through both ER subtypes. Ongoing mutagenesis studies should help define the molecular and structural differences that are responsible for these unanticipated results. The passive antagonism mechanism suggests a novel approach to the design of ligands that selectively antagonize the two ER subtypes. Such ligands may have novel therapeutic properties that can be exploited to prevent or treat breast cancer.