title: Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA.
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-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.
authors.affiliation: Department of Pharmacology, and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908-0735, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Chandra
authors.forename: Pengxiang
authors.initials: P
authors.lastname: Huang
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Hamuro
authors.forename: Srilatha
authors.initials: S
authors.lastname: Raghuram
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
authors.forename: Fraydoon
authors.initials: F
authors.lastname: Rastinejad
mesh_terms: 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*
chemical_list: D008024:Ligands; D046912:Multiprotein Complexes; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D004247:DNA