1. Department of Pharmacology, and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908-0735, USA
2. ExSAR Corporation, 11 Deer Park Drive, Suite 103, Monmouth Junction, New Jersey 08852, USA
3. Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA
4. These authors contributed equally to this work.

Correspondence to: Correspondence and requests for materials should be addressed to F.R. (Email: fr9c@virginia.edu).

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- 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- and RXR- as a heterodimer bound to DNA, ligands and coactivator peptides. PPAR- and RXR- form a non-symmetric complex, allowing the ligand-binding domain (LBD) of PPAR- to contact multiple domains in both proteins. Three interfaces link PPAR- and RXR-, including some that are DNA dependent. The PPAR- 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.

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