Asymmetry in the PPARγ/RXRα Crystal Structure Reveals the Molecular Basis of Heterodimerization among Nuclear Receptors

The nuclear receptor PPAR gamma /RXR alpha heterodimer regulates glucose and lipid homeostasis and is the target for the antidiabetic drugs GI262570 and the thiazolidinediones (TZDs). We report the crystal structures of the PPAR gamma and RXR alpha LBDs complexed to the RXR ligand 9-cis-retinoic acid (9cRA), the PPAR gamma agonist rosiglitazone or GI262570, and coactivator peptides. The PPAR gamma /RXR alpha heterodimer is asymmetric, with each LBD deviated similar to 10 degree from the C2 symmetry, allowing the PPAR gamma AF-2 helix to interact with helices 7 and 10 of RXR alpha . The heterodimer interface is composed of conserved motifs in PPAR gamma and RXR alpha that form a coiled coil along helix 10 with additional charge interactions from helices 7 and 9. The structures provide a molecular understanding of the ability of RXR to heterodimerize with many nuclear receptors and of the permissive activation of the PPAR gamma /RXR alpha heterodimer by 9cRA.