Exploring the mechanism of PPAR? phosphorylation mediated by CDK5.
Peroxisome proliferator-activated receptor gamma (PPAR?) is a nuclear receptor with a key role in metabolic processes and is target of CDK5 kinase phosphorylation at S245 (S273 in PPAR? isoform 2), thereby inducing insulin resistance. A remarkable effort has been addressed to find PPAR? 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 PPAR?-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 PPAR? ligands that inhibit S245 phosphorylation are not in direct contact with these residues; but induce structural modifications in PPAR?:CDK5/p25 interface. In summary, our PPAR? and CDK5/p25 interaction analyses open new possibilities for the rational design of novel inhibitors that impair S245 phosphorylation.
Mesh Terms:
Animals, Binding Sites, Cyclin-Dependent Kinase 5, Humans, Ligands, Models, Molecular, Multiprotein Complexes, Mutation, PPAR gamma, Phosphorylation, Protein Binding, Protein Conformation
Animals, Binding Sites, Cyclin-Dependent Kinase 5, Humans, Ligands, Models, Molecular, Multiprotein Complexes, Mutation, PPAR gamma, Phosphorylation, Protein Binding, Protein Conformation
J Struct Biol
Date: Dec. 01, 2018
PubMed ID: 31319193
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