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Structural Basis for the Regulation of PPAR? Activity by Imatinib.


ABSTRACT: Imatinib is an effective anticancer drug for the treatment of leukemia. Interestingly, when an FDA-approved drug library was tested for agents that block peroxisome proliferator-activated receptor ? (PPAR?) phosphorylation at Ser245 to evaluate possibilities of antidiabetic drug repositioning, imatinib was determined as a PPAR? antagonist ligand. However, it is not well understood how imatinib binds to PPAR? or would improve insulin sensitivity without classical agonism. Here, we report the crystal structure of the PPAR? R288A mutant in complex with imatinib. Imatinib bound to Arm2 and Arm3 regions in the ligand-binding domain (LBD) of PPAR?, of which the Arm3 region is closely related to the inhibition of PPAR? phosphorylation at Ser245. The binding of imatinib in LBD induced a stable conformation of helix H2' and the ? loop compared with the ligand-free state. In contrast, imatinib does not interact with Tyr473 on PPAR? helix H12, which is important for the classical agonism associated with side effects. Our study provides new structural insights into the PPAR? regulation by imatinib and may contribute to the development of new antidiabetic drugs targeting PPAR? while minimizing known side effects.

SUBMITTER: Jang JY 

PROVIDER: S-EPMC6803859 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Structural Basis for the Regulation of PPARγ Activity by Imatinib.

Jang Jun Young JY   Kim Hyun-Jung HJ   Han Byung Woo BW  

Molecules (Basel, Switzerland) 20191001 19


Imatinib is an effective anticancer drug for the treatment of leukemia. Interestingly, when an FDA-approved drug library was tested for agents that block peroxisome proliferator-activated receptor γ (PPARγ) phosphorylation at Ser245 to evaluate possibilities of antidiabetic drug repositioning, imatinib was determined as a PPARγ antagonist ligand. However, it is not well understood how imatinib binds to PPARγ or would improve insulin sensitivity without classical agonism. Here, we report the crys  ...[more]

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