TY - JOUR
T1 - Insights into PPARγ phosphorylation and its inhibition mechanism
AU - Montanari, Roberta
AU - Capelli, Davide
AU - Yamamoto, Keiko
AU - Awaishima, Hirono
AU - Nishikata, Kimina
AU - Barendregt, Arjan
AU - Heck, Albert J R
AU - Loiodice, Fulvio
AU - Altieri, Fabio
AU - Paiardini, Alessandro
AU - Grotessi, Alessandro
AU - Pirone, Luciano
AU - Pedone, Emilia Maria
AU - Peiretti, Franck
AU - Brunel, Jean Michel
AU - Itoh, Toshimasa
AU - Pochetti, Giorgio
PY - 2020/4/2
Y1 - 2020/4/2
N2 - PPARγ represents a key target for the treatment of type II diabetes and metabolic syndrome. Synthetic antidiabetic drugs activating PPARγ are accompanied by serious undesirable side effects related to their agonism. In the search for new PPARγ regulators, inhibitors of PPARγ phosphorylation on S245 mediated by CDK5 represent an opportunity for the development of an improved generation of anti-diabetic drugs acting through this nuclear receptor. We have employed a multi-disciplinary approach, including protein-protein docking, X-ray, NMR, HDX, MD simulations and site-directed mutagenesis to investigate conformational changes in PPARγ that impair the ability of CDK5 to interact with PPARγ and hence inhibit PPARγ phosphorylation. Finally, we describe an alternate inhibition mechanism adopted by a ligand bound far from the phosphorylation site.
AB - PPARγ represents a key target for the treatment of type II diabetes and metabolic syndrome. Synthetic antidiabetic drugs activating PPARγ are accompanied by serious undesirable side effects related to their agonism. In the search for new PPARγ regulators, inhibitors of PPARγ phosphorylation on S245 mediated by CDK5 represent an opportunity for the development of an improved generation of anti-diabetic drugs acting through this nuclear receptor. We have employed a multi-disciplinary approach, including protein-protein docking, X-ray, NMR, HDX, MD simulations and site-directed mutagenesis to investigate conformational changes in PPARγ that impair the ability of CDK5 to interact with PPARγ and hence inhibit PPARγ phosphorylation. Finally, we describe an alternate inhibition mechanism adopted by a ligand bound far from the phosphorylation site.
U2 - 10.1021/acs.jmedchem.0c00048
DO - 10.1021/acs.jmedchem.0c00048
M3 - Article
C2 - 32239932
SN - 0022-2623
VL - 63
SP - 4811
EP - 4823
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -