Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA.
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.
Chandra
Vikas
V
Department of Pharmacology, and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908-0735, USA.
Huang
Pengxiang
P
Hamuro
Yoshitomo
Y
Raghuram
Srilatha
S
Wang
Yongjun
Y
Burris
Thomas P
TP
Rastinejad
Fraydoon
F
D000494:Allosteric Regulation; D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism*; D047495:PPAR gamma / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D020218:Response Elements / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000737:chemistry* / Q000378:metabolism*
D008024:Ligands; D046912:Multiprotein Complexes; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D004247:DNA