Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA.

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Bibliographic Details
Title:	Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA.
Authors:	Chandra, Vikas, Huang, Pengxiang, Hamuro, Yoshitomo, Raghuram, Srilatha, Wang, Yongjun, Burris, Thomas P., Rastinejad, Fraydoon
Source:	Nature. 11/20/2008, Vol. 456 Issue 7220, p350-356. 7p. 5 Diagrams.
Subjects:	Molecular structure, Nuclear receptors (Biochemistry), Gene expression, Transcription factors, Ligand binding (Biochemistry), DNA-binding proteins, Peroxisomes, Scientific method
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. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

Description
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. [ABSTRACT FROM AUTHOR]
ISSN:	00280836
DOI:	10.1038/nature07413