Abstract
Repression of gene transcription by the nuclear receptor Rev-erbα plays an integral role in the core molecular circadian clock. We report the crystal structure of a nuclear receptor–co-repressor (N-CoR) interaction domain 1 (ID1) peptide bound to truncated human Rev-erbα ligand-binding domain (LBD). The ID1 peptide forms an unprecedented antiparallel β-sheet with Rev-erbα, as well as an α-helix similar to that seen in nuclear receptor ID2 crystal structures but out of register by four residues. Comparison with the structure of Rev-erbβ bound to heme indicates that ID1 peptide and heme induce substantially different conformational changes in the LBD. Although heme is involved in Rev-erb repression, the structure suggests that Rev-erbα could also mediate repression via ID1 binding in the absence of heme. The previously uncharacterized secondary structure induced by ID1 peptide binding advances our understanding of nuclear receptor–co-repressor interactions.
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Acknowledgements
This work was supported by the US National Institutes of Health grant DK45586 (M.A.L.) and by the Penn–GlaxoSmithKline Academic Drug Discovery Initiative. We thank N. Wu for critically reading the manuscript and T.B. Stanley and T.M. Willson for useful discussions.
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D.J.P. performed the fluorescence energy transfer assays, M.H.L. and S.P.W. performed structure-based construct design, T.M.B. grew the cells, J.B. purified the protein, V.M. crystallized the protein complex, R.T.G. and R.T.N. solved the structure, R.T.G. refined and analyzed the structures, C.A.P. performed the mammalian two-hybrid assay, X.H. performed the thyroid receptor analysis, S.P.W. and R.T.N. provided critical review and C.A.P., R.T.G., M.H.L. and M.A.L. wrote and edited the manuscript.
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Phelan, C., Gampe, R., Lambert, M. et al. Structure of Rev-erbα bound to N-CoR reveals a unique mechanism of nuclear receptor–co-repressor interaction. Nat Struct Mol Biol 17, 808–814 (2010). https://doi.org/10.1038/nsmb.1860
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DOI: https://doi.org/10.1038/nsmb.1860
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