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Proteins. 2010 Mar;78(4):873-87. doi: 10.1002/prot.22613.

Molecular mechanism of allosteric communication in the human PPARalpha-RXRalpha heterodimer.

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Laboratory of Chemistry, Department of Biosciences, University of Kuopio, Kuopio FIN-70211, Finland.


The peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor (NR) that forms a heterodimeric transcription factor complex with the retinoid X receptor alpha (RXRalpha). The phenomenon that the heterodimer can be activated by both PPARalpha and RXRalpha 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 PPARalpha-RXRalpha heterodimer ligand-binding domains (LBDs) without ligands, with agonistic ligand bound to RXRalpha or PPARalpha, and ligand bound to both receptors. Fluctuation calculations and structural clustering analysis of the heterodimer MD simulations showed that ligand binding to RXRalpha decreases fluctuations of large parts of PPARalpha, 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 RXRalpha 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 RXRalpha ligand binding-induced stabilization of PPARalpha coactivator binding site has a role in the permissive and synergistic activation of the PPARalpha-RXRalpha heterodimer. Proteins 2010.

[Indexed for MEDLINE]

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