Cargando…

Structural Basis for the Regulation of PPARγ Activity by Imatinib

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, imati...

Descripción completa

Detalles Bibliográficos
Autores principales: Jang, Jun Young, Kim, Hyun-Jung, Han, Byung Woo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803859/
https://www.ncbi.nlm.nih.gov/pubmed/31581474
http://dx.doi.org/10.3390/molecules24193562
_version_ 1783461041844256768
author Jang, Jun Young
Kim, Hyun-Jung
Han, Byung Woo
author_facet Jang, Jun Young
Kim, Hyun-Jung
Han, Byung Woo
author_sort Jang, Jun Young
collection PubMed
description 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 crystal structure of the PPARγ R288A mutant in complex with imatinib. Imatinib bound to Arm2 and Arm3 regions in the ligand-binding domain (LBD) of PPARγ, of which the Arm3 region is closely related to the inhibition of PPARγ phosphorylation at Ser245. The binding of imatinib in LBD induced a stable conformation of helix H2′ and the Ω loop compared with the ligand-free state. In contrast, imatinib does not interact with Tyr473 on PPARγ helix H12, which is important for the classical agonism associated with side effects. Our study provides new structural insights into the PPARγ regulation by imatinib and may contribute to the development of new antidiabetic drugs targeting PPARγ while minimizing known side effects.
format Online
Article
Text
id pubmed-6803859
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-68038592019-11-18 Structural Basis for the Regulation of PPARγ Activity by Imatinib Jang, Jun Young Kim, Hyun-Jung Han, Byung Woo Molecules Article 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 crystal structure of the PPARγ R288A mutant in complex with imatinib. Imatinib bound to Arm2 and Arm3 regions in the ligand-binding domain (LBD) of PPARγ, of which the Arm3 region is closely related to the inhibition of PPARγ phosphorylation at Ser245. The binding of imatinib in LBD induced a stable conformation of helix H2′ and the Ω loop compared with the ligand-free state. In contrast, imatinib does not interact with Tyr473 on PPARγ helix H12, which is important for the classical agonism associated with side effects. Our study provides new structural insights into the PPARγ regulation by imatinib and may contribute to the development of new antidiabetic drugs targeting PPARγ while minimizing known side effects. MDPI 2019-10-01 /pmc/articles/PMC6803859/ /pubmed/31581474 http://dx.doi.org/10.3390/molecules24193562 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jang, Jun Young
Kim, Hyun-Jung
Han, Byung Woo
Structural Basis for the Regulation of PPARγ Activity by Imatinib
title Structural Basis for the Regulation of PPARγ Activity by Imatinib
title_full Structural Basis for the Regulation of PPARγ Activity by Imatinib
title_fullStr Structural Basis for the Regulation of PPARγ Activity by Imatinib
title_full_unstemmed Structural Basis for the Regulation of PPARγ Activity by Imatinib
title_short Structural Basis for the Regulation of PPARγ Activity by Imatinib
title_sort structural basis for the regulation of pparγ activity by imatinib
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803859/
https://www.ncbi.nlm.nih.gov/pubmed/31581474
http://dx.doi.org/10.3390/molecules24193562
work_keys_str_mv AT jangjunyoung structuralbasisfortheregulationofppargactivitybyimatinib
AT kimhyunjung structuralbasisfortheregulationofppargactivitybyimatinib
AT hanbyungwoo structuralbasisfortheregulationofppargactivitybyimatinib