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Updated: May 6, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 16, 2013

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

Vikas Chandra1, Pengxiang Huang, Yoshitomo Hamuro

  • 1Department of Pharmacology, and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908-0735, USA.

Nature
|December 2, 2008
PubMed

Insights

This study reveals how intact peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and retinoid X receptor-alpha (RXR-alpha) heterodimers bind DNA and ligands. The PPAR-gamma ligand-binding domain cooperates with DNA-binding domains to enhance gene regulation.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Genetics

Background:

  • Nuclear receptors are transcription factors regulating gene expression.
  • Peroxisome proliferator-activated receptors (PPARs) heterodimerize with retinoid X receptors (RXRs).
  • PPAR-gamma is a drug target linked to insulin sensitization, but its domain cooperation is poorly understood.

Purpose of the Study:

  • To elucidate the structural basis of intact PPAR-gamma/RXR-alpha heterodimer function.
  • To understand how multiple receptor domains cooperate in DNA and ligand binding.
  • To provide insights into PPAR-gamma's role in insulin sensitization.

Main Methods:

  • X-ray crystallography was used to determine the structures of intact PPAR-gamma and RXR-alpha heterodimers.
  • The structures were determined in complex with DNA response elements, ligands, and coactivator peptides.

Main Results:

  • The intact PPAR-gamma/RXR-alpha heterodimer forms a non-symmetric complex.
  • Three interfaces link PPAR-gamma and RXR-alpha, with some being DNA-dependent.
  • The PPAR-gamma ligand-binding domain (LBD) interacts with both DNA-binding domains (DBDs) to enhance DNA binding.
  • The A/B segments of the receptors are highly dynamic and lack stable structures.

Conclusions:

  • The structural data reveals a novel mechanism of receptor-DNA interaction involving domain cooperation.
  • Understanding these interactions is crucial for developing targeted therapies for metabolic diseases.
  • The dynamic nature of A/B segments despite their functional importance warrants further investigation.

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