6KTM

The ligand-free structure of human PPARgamma ligand-binding domain R288A mutant in the presence of the SRC-1 coactivator peptide

6KTM の概要

• エントリーDOI: 10.2210/pdb6ktm/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, 16-mer peptide from Nuclear receptor coactivator 1 (3 entities in total)
• 機能のキーワード: type 2 diabetes mellitus, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34099.42

構造登録者

Jang, J.Y.,Han, B.W. (登録日: 2019-08-28, 公開日: 2020-02-05, 最終更新日: 2023-11-22)

主引用文献

Jang, J.Y.,Kim, H.J.,Han, B.W.
Structural Basis for the Regulation of PPAR gamma Activity by Imatinib.
Molecules, 24:-, 2019

PubMed 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 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.

PubMed: 31581474
DOI: 10.3390/molecules24193562

実験手法

X-RAY DIFFRACTION (2.7 Å)