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...
Autores principales: | , , |
---|---|
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 |