Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism

The R, R enantiomer of 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC) exerts opposite effects on the transcriptional activity of the two estrogen receptor (ER) subtypes, ERalpha and ERbeta. THC acts as an ERalpha agonist and as an ERbeta antagonist. We have determined the crystal structures of the ERalpha ligand binding domain (LBD) bound to both THC and a fragment of the transcriptional coactivator GRIP1, and the ERbeta LBD bound to THC. THC stabilizes a conformation of the ERalpha LBD that permits coactivator association and a conformation of the ERbeta LBD that prevents coactivator association. A comparison of the two structures, taken together 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'.