Repression of gene transcription by nuclear receptors is mediated by interactions with co-repressor proteins such as SMRT and N-CoR1,2, which in turn recruit histone deacetylases to the chromatin3,4,5. Aberrant interactions between nuclear receptors and co-repressors contribute towards acute promyelocytic leukaemia and thyroid hormone resistance syndrome6,7,8. The binding of co-repressors to nuclear receptors occurs in the unliganded state, and can be stabilized by antagonists9. Here we report the crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor-α ligand-binding domain bound to the antagonist GW6471 and a SMRT co-repressor motif. In this structure, the co-repressor motif adopts a three-turn α-helix that prevents the carboxy-terminal activation helix (AF-2) of the receptor from assuming the active conformation. Binding of the co-repressor motif is further reinforced by the antagonist, which blocks the AF-2 helix from adopting the active position. Biochemical analyses and structure-based mutagenesis indicate that this mode of co-repressor binding is highly conserved across nuclear receptors.
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We thank B. Wisely and R. Bledsoe for making co-repressor expression constructs in early crystallization studies; W. Burkart and M. Moyer for protein sequencing; M. Iannone for compound characterizations; G. Waitt and C. Wagner for mass spectroscopy and amino-acid content analysis; and J. Chrzas and A. Howard for assistance with data collections at 17-ID. Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, and Office of Science. We also thank L. Kuyper and D. Eggleston for support and critical reading of the manuscript.
The authors declare no competing financial interests.
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Xu, H., Stanley, T., Montana, V. et al. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARα. Nature 415, 813–817 (2002). https://doi.org/10.1038/415813a
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