Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA

Vikas Chandra, Pengxiang Huang, Yoshitomo Hamuro, Srilatha Raghuram, Yongjun Wang, Thomas P. Burris and Fraydoon Rastinejad
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Vikas Chandra: and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908-0735, USA
Pengxiang Huang: and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908-0735, USA
Yoshitomo Hamuro: ExSAR Corporation, 11 Deer Park Drive, Suite 103, Monmouth Junction, New Jersey 08852, USA
Srilatha Raghuram: and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908-0735, USA
Yongjun Wang: Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA
Thomas P. Burris: Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA
Fraydoon Rastinejad: and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908-0735, USA

Nature, 2008, vol. 456, issue 7220, 350-356

Abstract: 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.

Date: 2008
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DOI: 10.1038/nature07413

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