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

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-gamma 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-gamma and RXR-alpha as a heterodimer bound to DNA, ligands and coactivator peptides. PPAR-gamma and RXR-alpha form a non- symmetric complex, allowing the ligand- binding domain ( LBD) of PPAR-gamma to contact multiple domains in both proteins. Three interfaces link PPAR-gamma and RXR-alpha, including some that are DNA dependent. The PPAR-gamma 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.