6DHA

Crystal Structure of Human PPARgamma Ligand Binding Domain in Complex with Hydroxy Pioglitazone (M-IV)

6DHA の概要

• エントリーDOI: 10.2210/pdb6dha/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, Hydroxy Pioglitazone (M-IV), nonanoic acid, ... (4 entities in total)
• 機能のキーワード: nuclear receptors, tzds, drug design, therapeutic targets, transcription, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63055.39

構造登録者

Shang, J.,Mosure, S.A.,Kojetin, D.J. (登録日: 2018-05-18, 公開日: 2019-03-13, 最終更新日: 2023-10-11)

主引用文献

Mosure, S.A.,Shang, J.,Eberhardt, J.,Brust, R.,Zheng, J.,Griffin, P.R.,Forli, S.,Kojetin, D.J.
Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPAR gamma Drug Pioglitazone.
J. Med. Chem., 62:2008-2023, 2019

PubMed Abstract: Pioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), yet it remains unclear how in vivo Pio metabolites affect PPARγ structure and function. Here, we present a structure-function comparison of Pio and its most abundant in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in co-regulator recruitment assays. X-ray crystallography and molecular docking analysis of PioOH-bound PPARγ ligand-binding domain revealed an altered hydrogen bonding network, including the formation of water-mediated bonds, which could underlie its altered biochemical phenotype. NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry analysis coupled to activity assays revealed that PioOH better stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and better enhances co-activator binding, affording slightly better transcriptional efficacy. These results indicating that Pio hydroxylation affects its potency and efficacy as a PPARγ agonist contributes to our understanding of PPARγ-drug metabolite interactions.

PubMed: 30676741
DOI: 10.1021/acs.jmedchem.8b01573

実験手法

X-RAY DIFFRACTION (1.88 Å)