Molecular Recognition of PPARγ by Kinase Cdk5/p25: Insights from a Combination of Protein–Protein Docking and Adaptive Biasing Force Simulations

The
peroxisome proliferator-activated receptor γ (PPARγ)
is an important transcription factor that plays a major role in the
regulation of glucose and lipid metabolisms and has, therefore, many
implications in modern-life metabolic disorders such as diabetes,
obesity, and cardiovascular diseases. Phosphorylation of PPARγ
by the cyclin-dependent 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 protein–protein
interactions between Cdk5/p25 and PPARγ can be an important
asset for better understanding of the molecular basis of the Cdk5-meditated
phosphorylation of PPARγ and its inhibition. By means of a computational
approach that combines protein–protein docking and adaptive
biasing force molecular dynamics simulations, we obtained PPARγ-Cdk5/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 two distal docking sites, comprising the PPARγ Ω-loop
and Cdk5 N-terminal lobe and the PPARγ β-sheet and Cdk5
C-terminal lobe. These sites are related to PPARγ transactivation
and directly interact with PPARγ ligands. Our results suggest
that β-sheets and Ω-loop stabilization promoted by PPARγ
agonists could be important to inhibit Cdk5-mediated phosphorylation.