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, Fraydoon Rastinejad

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484 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)350-356
Number of pages7
JournalNature
Volume456
Issue number7220
DOIs
StatePublished - Nov 20 2008

ASJC Scopus subject areas

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    Chandra, V., Huang, P., Hamuro, Y., Raghuram, S., Wang, Y., Burris, T. P., & Rastinejad, F. (2008). Structure of the intact PPAR-γ-RXR-α nuclear receptor complex on DNA. Nature, 456(7220), 350-356. https://doi.org/10.1038/nature07413