Structural Basis for the Deactivation of the Estrogen-related Receptor γ by Diethylstilbestrol or 4-Hydroxytamoxifen and Determinants of Selectivity

The estrogen-related receptor (ERR) γ behaves as a constitutive activator of transcription. Although no natural ligand is known, ERRγ is deactivated by the estrogen receptor (ER) agonist diethylstilbestrol and the selective ER modulator 4-hydroxytamoxifen but does not significantly respond to estradiol or raloxifene. Here we report the crystal structures of the ERRγ ligand binding domain (LBD) complexed with diethylstilbestrol or 4-hydroxytamoxifen. Antagonist binding to ERRγ results in a rotation of the side chain of Phe-435 that partially fills the cavity of the apoLBD. The new rotamer of Phe-435 displaces the “activation helix” (helix 12) from the agonist position observed in the absence of ligand. In contrast to the complexes of the ERα LBD with 4-hydroxytamoxifen or raloxifene, helix 12 of antagonist-bound ERRγ does not occupy the coactivator groove but appears to be completely dissociated from the LBD body. Comparison of the ligand-bound LBDs of ERRγ and ERα reveals small but significant differences in the architecture of the ligand binding pockets that result in a slightly shifted binding position of diethylstilbestrol and a small rotation of 4-hydroxytamoxifen in the cavity of ERRγ relative to ERα. Our results provide detailed molecular insight into the conformational changes occurring upon binding of synthetic antagonists to the constitutive orphan receptor ERRγ and reveal structural differences with ERs that explain why ERRγ does not bind estradiol or raloxifene and will help to design new selective antagonists.