Exploring the mechanism of PPARγ phosphorylation mediated by CDK5

J Struct Biol. 2019 Sep 1;207(3):317-326. doi: 10.1016/j.jsb.2019.07.007. Epub 2019 Jul 15.

Abstract

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.

Keywords: Cyclin-dependent kinase 5; Non-contiguous phosphorylation site; PPARγ ligands; PPARγ phosphorylation; PPARγ:CDK5/p25 docking model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Cyclin-Dependent Kinase 5 / chemistry*
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / metabolism
  • Humans
  • Ligands
  • Models, Molecular
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Mutation
  • PPAR gamma / chemistry*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Conformation*

Substances

  • Ligands
  • Multiprotein Complexes
  • PPAR gamma
  • Cyclin-Dependent Kinase 5
  • CDK5 protein, human