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J. Biol. Chem., Vol. 279, Issue 32, 33639-33646, August 6, 2004
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Structural Basis for the Deactivation of the Estrogen-related Receptor 
by Diethylstilbestrol or 4-Hydroxytamoxifen and Determinants of Selectivity*
From the Département de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, B. P. 10142, 67404 Illkirch, France
The estrogen-related receptor (ERR) 
behaves as a constitutive activator of transcription. Although no natural ligand is known, ERR 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 ERR ligand binding domain (LBD) complexed with diethylstilbestrol or 4-hydroxytamoxifen. Antagonist binding to ERR 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 ER
LBD with 4-hydroxytamoxifen or raloxifene, helix 12 of antagonist-bound ERR does not occupy the coactivator groove but appears to be completely dissociated from the LBD body. Comparison of the ligand-bound LBDs of ERR and ER 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 ERR relative to ER. Our results provide detailed molecular insight into the conformational changes occurring upon binding of synthetic antagonists to the constitutive orphan receptor ERR and reveal structural differences with ERs that explain why ERR does not bind estradiol or raloxifene and will help to design new selective antagonists.
Received for publication, February 27, 2004 , and in revised form, May 17, 2004.
The atomic coordinates and structure factors (code 1TFC apoLBD (refined structure)), 1S9P LBD·DES), 1S9Q LBD·4-OHT (crystal form 1)), 1VJB LBD·4-OHT (crystal form 2)).) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
* This work was supported by a Marie-Curie individual fellowship of the European Community (to H. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 33-3-88-65-32-20; Fax: 33-3-88-65-32-76; E-mail: moras{at}igbmc.u-strasbg.fr.
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