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

Journal Article · Fri Jan 09 04:00:00 EST 2009 · Nature

DOI:https://doi.org/10.1038/nature07413· OSTI ID:1007014

Chandra, Vikas; Huang, Pengxiang; Hamuro, Yoshitomo; Raghuram, Srilatha; Wang, Yongjun; Burris, Thomas P; Rastinejad, Fraydoon ^[1]

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1. Penn. Bio.

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1007014
• Journal Information: Nature, Journal Name: Nature Journal Issue: 11, 2008 Vol. 456
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
DNA
DRUGS
ELEMENTS
GENES
INSULIN
INTERFACES
LIGANDS
PEPTIDES
PROTEINS
RECEPTORS
TARGETS
TRANSCRIPTION FACTORS