Molecular mechanism of allosteric communication in the human PPARα-RXRα heterodimer

The peroxisome proliferator‐activated receptor α (PPARα) is a nuclear receptor (NR) that forms a heterodimeric transcription factor complex with the retinoid X receptor α (RXRα). The phenomenon that the heterodimer can be activated by both PPARα and RXRα ligands, while both ligands have a synergistic effect on its activity suggests that there is an allosteric communication within the heterodimer. In this study, the molecular mechanism of this allosteric signaling was studied by molecular dynamics (MD) simulations and some of the residues involved in this communication were tested experimentally. Multiple MD simulations were done for the PPARα‐RXRα heterodimer ligand‐binding domains (LBDs) without ligands, with agonistic ligand bound to RXRα or PPARα, and ligand bound to both receptors. Fluctuation calculations and structural clustering analysis of the heterodimer MD simulations showed that ligand binding to RXRα decreases fluctuations of large parts of PPARα, most notably helices 3 and 4 at the coactivator binding site, which presumably stabilizes the coactivator binding to heterodimer complex. The dynamics of helix 8–9 loop and helix 10/11 located at the heterodimeric interface were affected by RXRα ligand binding, suggesting that these parts of the dimer are involved in allosteric communication. Experimental data complemented this view by showing that a large set of residues at the heterodimerization surface has a role in the communication. These results provided evidence that RXRα ligand binding‐induced stabilization of PPARα coactivator binding site has a role in the permissive and synergistic activation of the PPARα‐RXRα heterodimer. Proteins 2010. © 2009 Wiley‐Liss, Inc.