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

Research output: Contribution to journalArticle

454 Citations (Scopus)

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

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Retinoid X Receptors
Peroxisome Proliferator-Activated Receptors
Cytoplasmic and Nuclear Receptors
DNA
Ligands
Response Elements
Transcriptional Activation
Transcription Factors
Insulin
Gene Expression
Peptides
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

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

Structure of the intact PPAR-γ-RXR-α nuclear receptor complex on DNA. / Chandra, Vikas; Huang, Pengxiang; Hamuro, Yoshitomo; Raghuram, Srilatha; Wang, Yongjun; Burris, Thomas P.; Rastinejad, Fraydoon.

In: Nature, Vol. 456, No. 7220, 20.11.2008, p. 350-356.

Research output: Contribution to journalArticle

Chandra, V, Huang, P, Hamuro, Y, Raghuram, S, Wang, Y, Burris, TP & Rastinejad, F 2008, 'Structure of the intact PPAR-γ-RXR-α nuclear receptor complex on DNA', Nature, vol. 456, no. 7220, pp. 350-356. https://doi.org/10.1038/nature07413
Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP et al. Structure of the intact PPAR-γ-RXR-α nuclear receptor complex on DNA. Nature. 2008 Nov 20;456(7220):350-356. https://doi.org/10.1038/nature07413
Chandra, Vikas ; Huang, Pengxiang ; Hamuro, Yoshitomo ; Raghuram, Srilatha ; Wang, Yongjun ; Burris, Thomas P. ; Rastinejad, Fraydoon. / Structure of the intact PPAR-γ-RXR-α nuclear receptor complex on DNA. In: Nature. 2008 ; Vol. 456, No. 7220. pp. 350-356.
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