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J. Biol. Chem., Vol. 282, Issue 14, 10449-10455, April 6, 2007

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Structural Insights into Corepressor Recognition by Antagonist-bound Estrogen Receptors^*

Nina Heldring, Supported by grants from the Swedish Research Council and the Swedish Cancer Society¹, Tanya Pawson, Donald McDonnell^¶, Eckardt Treuter², Jan-Åke Gustafsson³, and Ashley C. W. Pike, Supported by Wellcome Trust Career Development Award Grant 064803⁴

From the Department of Biosciences and Nutrition, Karolinska Institutet, S-14157 Huddinge, Sweden, Structural Biology Laboratory, University of York, York YO10 5YW, United Kingdom, and ^¶Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

Direct recruitment of transcriptional corepressors to estrogen receptors (ER) is thought to contribute to the tissue-specific effects of clinically important ER antagonists. Here, we present the crystal structures of two affinity-selected peptides in complex with antagonist-bound ER ligand-binding domain. Both peptides adopt helical conformations, bind along the activation function 2 coregulator interaction surface, and mimic corepressor (CoRNR) sequence motif binding. Peptide binding is weak in a wild-type context but significantly enhanced by removal of ER helix 12. This region contains a previously unrecognized CoRNR motif that is able to compete with corepressors for binding to activation function 2, thereby providing a structural explanation for the poor ability of ER to directly interact with classical corepressors. Furthermore, the ability of other sequence motifs to mimic corepressor binding raises the possibility that coregulators do not necessarily require CoRNR motifs for direct recruitment to antagonist-bound ER.

Received for publication, December 13, 2006 , and in revised form, February 1, 2007.

The atomic coordinates and structure factors (code 2JFA and 2JF9) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

² Supported by grants from the Swedish Cancer Society and the European Network of Excellence CASCADE.

³ Supported by grants from the Swedish Research Council, the Swedish Cancer Society, and the European Network of Excellence CASCADE.

¹ To whom correspondence may be addressed. Tel.: 47-8-6089155; Fax: 47-8-7745538; E-mail: nina.heldring{at}biosci.ki.se. ⁴ To whom correspondence may be addressed: Structural Genomics Consortium, Botnar Research Centre, University of Oxford, Headington, Oxford OX3 7LD, UK. Tel.: 44-1865-227358; Fax: 44-1865-737231; E-mail: ashley.pike{at}sgc.ox.ac.uk.

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