Abstract
Nuclear receptors are multi-domain transcription factors that bind to DNA elements from which they regulate gene expression. The peroxisome proliferator-activated receptors (PPARs) form heterodimers with the retinoid X receptor (RXR), and PPAR-γ has been intensively studied as a drug target because of its link to insulin sensitization. Previous structural studies have focused on isolated DNA or ligand-binding segments, with no demonstration of how multiple domains cooperate to modulate receptor properties. Here we present structures of intact PPAR-γ and RXR-α as a heterodimer bound to DNA, ligands and coactivator peptides. PPAR-γ and RXR-α form a non-symmetric complex, allowing the ligand-binding domain (LBD) of PPAR-γ to contact multiple domains in both proteins. Three interfaces link PPAR-γ and RXR-α, including some that are DNA dependent. The PPAR-γ LBD cooperates with both DNA-binding domains (DBDs) to enhance response-element binding. The A/B segments are highly dynamic, lacking folded substructures despite their gene-activation properties.
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Change history
20 November 2008
In the AOP version of this paper, the Protein Data Bank accession number 3E00 was erroneously listed as 3EOO. This was corrected for print on 20 November 2008.
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Acknowledgements
We thank K. S. Molnar, S. J. Tuske and S. J. Coales for providing assistance with the H/D-Ex studies; M. Chruszcz and W. Minor for assistance with diffraction data processing and analysis; P. Rogers for analysis of mutant receptor expression; and P. Griffin for providing BVT.13.
Author Contributions V.C. expressed, purified and crystallized the samples, and with P.H. collected data and solved the structure. Y.H. performed the H/D-Ex work. S.R. provided the expression systems. Y.W. and T.P.B. performed the electrophoretic mobility shift assay and transcription reporter assays. F.R. supervised the work and wrote the manuscript.
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Chandra, V., Huang, P., Hamuro, Y. et al. Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA. Nature 456, 350–356 (2008). https://doi.org/10.1038/nature07413
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DOI: https://doi.org/10.1038/nature07413