Molecular Recognition of PPAR# by the Kinase Cdk5/ p25

The peroxisome proliferatoractivated receptor γ (PPARγ) is an important transcription factor that plays a major role in the regulation of glucos e and lipid metabolisms and has, therefore, many implications in modernlife metabolic disorders such as diabetes, obesity, and cardiovascular diseases. Phosphorylation of PPARγ by the cyclindependent kinase 5 (Cdk5) has been recently proved to promote obesity and loss of insulin sensitivity. The inhibition of this reaction is currently being pursued to develop PPARγ ligands for type 2 diabetes treatments. The knowledge of the proteinprotein interactions between Cdk5/p25 and PPARγ can be an important asset for better understanding of the molecular basis of the Cdk5meditated phosphorylation of PPARγ and its inhibition. By means of a computational approach that combines protein docking and adaptive biasing force molecular dynamics simulations, we obtained PPARγCdk5/p25 structural models that are consistent with the mechanism of the enzymatic reaction and with overall structural features of the full length PPARγ RXRα heterodimer bound to DNA. In addition to the active site, our model shows that the interacting regions between the two proteins should involve twodistal docking sites, comprised of the PPARγ Ω loop and Cdk5 Nterminal lobe and the PPARγ βsheetand Cdk5 Cterminal lobe. These sites are related to PPARγ transactivation and directly interact with PPARγ ligands. Our results suggest that β sheets and Ωloop stabilization promoted by PPARγ agonists could be important to inhibit Cdk5 mediated phosphorylation.


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