Exploring the mechanism of PPAR gamma phosphorylation mediated by CDK5

Autor(es)

Ribeiro Filho, V, H. ; Guerra, V, J. ; Cagliari, R. ^{[1, 2]} ; Batista, F. A. H. ^[1] ; Le Maire, A. ^[3] ; Oliveira, P. S. L. ^{[1, 2]} ; Figueira, A. C. M. ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Guerra, J., V, Ribeiro Filho, H., V, Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, BR-13083970 Campinas, SP - Brazil

^[2] Guerra, J., V, Ribeiro Filho, H., V, State Univ Campinas Unicamp, Grad Program Biosci & Technol Bioact Prod, Inst Biol, Campinas, SP - Brazil

^[3] Univ Montpellier, Ctr Biochim Struct CNRS, Montpellier - France

• Tipo de documento: Artigo Científico
• Fonte: Journal of Structural Biology; v. 207, n. 3, p. 317-326, SEP 1 2019.
• Citações Web of Science: 1

Resumo

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor with a key role in metabolic processes and is target of CDK5 kinase phosphorylation at 5245 (S273 in PPAR gamma isoform 2), thereby inducing insulin resistance. A remarkable effort has been addressed to find PPAR gamma 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 gamma-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 gamma ligands that inhibit 5245 phosphorylation are not in direct contact with these residues; but induce structural modifications in PPAR gamma:CDK5/p25 interface. In summary, our PPAR gamma and CDK5/p25 interaction analyses open new possibilities for the rational design of novel inhibitors that impair 5245 phosphorylation. (AU)

• Processo FAPESP: 16/22246-0 - Mecanismos de repressão do PPAR gama como alvo para combate ao diabetes e obesidade.
• Beneficiário: Ana Carolina Migliorini Figueira
• Modalidade de apoio: Auxílio à Pesquisa - Regular