Résumé
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•Interaction model of PPARγ and CDK5/p25 validated using mutagenesis.•CDK5 recognize a non-contiguous motif in PPARγ through PPARγ K261 residue.•PPARγ K263 and K265 residues form a distal docking site for CDK5 binding.•K261, K263 and K265 are conserved in mammals and are not polymorphic in humans.•S245 phosphorylation inhibitors induce a hydrophobic network in PPARγ.
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor with a key role in metabolic processes and is target of CDK5 kinase phosphorylation at S245 (S273 in PPARγ isoform 2), thereby inducing insulin resistance. A remarkable effort has been addressed to find PPARγ ligands that inhibit S245 phosphorylation, but the poor understanding in this field challenges the design of such ligands. Here, through computational and biophysical methods, we explored an experimentally validated model of PPARγ-CDK5 complex, and we presented K261, K263 or K265, which are conserved in mammals, as important anchor residues for this interaction. In addition, we observed, from structural data analysis, that PPARγ ligands that inhibit S245 phosphorylation are not in direct contact with these residues; but induce structural modifications in PPARγ:CDK5/p25 interface. In summary, our PPARγ and CDK5/p25 interaction analyses open new possibilities for the rational design of novel inhibitors that impair S245 phosphorylation.