PPARγrepresents a key target for the treatment of type 2 diabetes and metabolic syndrome. Synthetic antidiabetic drugs activating PPARγare accompanied by serious undesirable side effects related to their agonism. In the search for new PPARγregulators, inhibitors of PPARγphosphorylation on S245 mediated by CDK5 represent an opportunity for the development of an improved generation of antidiabetic drugs acting through this nuclear receptor. We have employed a multidisciplinary approach, including protein-protein docking, X-ray crystallography, NMR, HDX, MD simulations, and site-directed mutagenesis to investigate conformational changes in PPARγthat impair the ability of CDK5 to interact with PPARγand hence inhibit PPARγphosphorylation. Finally, we describe an alternative inhibition mechanism adopted by a ligand bound far from the phosphorylation site.

Insights into pparγphosphorylation and its inhibition mechanism / Montanari, R.; Capelli, D.; Yamamoto, K.; Awaishima, H.; Nishikata, K.; Barendregt, A.; Heck, A. J. R.; Loiodice, F.; Altieri, F.; Paiardini, A.; Grottesi, A.; Pirone, L.; Pedone, E.; Peiretti, F.; Brunel, J. M.; Itoh, T.; Pochetti, G.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 63:9(2020), pp. 4811-4823. [10.1021/acs.jmedchem.0c00048]

Insights into pparγphosphorylation and its inhibition mechanism

Montanari R.
;
Altieri F.;Paiardini A.;Grottesi A.;
2020

Abstract

PPARγrepresents a key target for the treatment of type 2 diabetes and metabolic syndrome. Synthetic antidiabetic drugs activating PPARγare accompanied by serious undesirable side effects related to their agonism. In the search for new PPARγregulators, inhibitors of PPARγphosphorylation on S245 mediated by CDK5 represent an opportunity for the development of an improved generation of antidiabetic drugs acting through this nuclear receptor. We have employed a multidisciplinary approach, including protein-protein docking, X-ray crystallography, NMR, HDX, MD simulations, and site-directed mutagenesis to investigate conformational changes in PPARγthat impair the ability of CDK5 to interact with PPARγand hence inhibit PPARγphosphorylation. Finally, we describe an alternative inhibition mechanism adopted by a ligand bound far from the phosphorylation site.
2020
amino acidsequence; biphenyl compounds; cyclin-dependent kinase 5; humans; molecular docking simulation; molecular dynamics simulation; mutagenesis, site-directed; mutation; nerve tissue proteins; PPAR gamma; phenylpropionates; phosphorylation; protein binding; protein conformation; serine
01 Pubblicazione su rivista::01a Articolo in rivista
Insights into pparγphosphorylation and its inhibition mechanism / Montanari, R.; Capelli, D.; Yamamoto, K.; Awaishima, H.; Nishikata, K.; Barendregt, A.; Heck, A. J. R.; Loiodice, F.; Altieri, F.; Paiardini, A.; Grottesi, A.; Pirone, L.; Pedone, E.; Peiretti, F.; Brunel, J. M.; Itoh, T.; Pochetti, G.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 63:9(2020), pp. 4811-4823. [10.1021/acs.jmedchem.0c00048]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1458055
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