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

Nature. 2008 Nov 20;456(7220):350-6. doi: 10.1038/nature07413.

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-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.

MeSH terms

  • Allosteric Regulation
  • Base Sequence
  • DNA / chemistry
  • DNA / genetics
  • DNA / metabolism*
  • Humans
  • Ligands
  • Models, Molecular
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / metabolism*
  • PPAR gamma / chemistry*
  • PPAR gamma / metabolism*
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Response Elements / genetics
  • Retinoid X Receptor alpha / chemistry*
  • Retinoid X Receptor alpha / metabolism*

Substances

  • Ligands
  • Multiprotein Complexes
  • PPAR gamma
  • Retinoid X Receptor alpha
  • DNA

Associated data

  • PDB/3DZU
  • PDB/3DZY
  • PDB/3E00