4XTA

MECHANISMS OF PPARgamma ACTIVATION BY NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

4XTA の概要

• エントリーDOI: 10.2210/pdb4xta/pdb
• 関連するPDBエントリー: 3SZ1 4XUH
• 分子名称: Peroxisome proliferator-activated receptor gamma, 2-[2,6-DICHLOROPHENYL)AMINO]BENZENEACETIC ACID (3 entities in total)
• 機能のキーワード: nuclear receptor, transcription factor, transcription
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: P37231
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64062.02

構造登録者

Puhl, A.C.,Webb, P.,Polikarpov, I. (登録日: 2015-01-23, 公開日: 2015-11-11, 最終更新日: 2024-02-28)

主引用文献

Puhl, A.C.,Milton, F.A.,Cvoro, A.,Sieglaff, D.H.,Campos, J.C.,Bernardes, A.,Filgueira, C.S.,Lindemann, J.L.,Deng, T.,Neves, F.A.,Polikarpov, I.,Webb, P.
Mechanisms of peroxisome proliferator activated receptor gamma regulation by non-steroidal anti-inflammatory drugs.
Nucl Recept Signal, 13:e004-e004, 2015

PubMed Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) display anti-inflammatory, antipyretic and analgesic properties by inhibiting cyclooxygenases and blocking prostaglandin production. Previous studies, however, suggested that some NSAIDs also modulate peroxisome proliferator activated receptors (PPARs), raising the possibility that such off target effects contribute to the spectrum of clinically relevant NSAID actions. In this study, we set out to understand how peroxisome proliferator activated receptor-γ (PPARγ/PPARG) interacts with NSAIDs using X-ray crystallography and to relate ligand binding modes to effects on receptor activity. We find that several NSAIDs (sulindac sulfide, diclofenac, indomethacin and ibuprofen) bind PPARγ and modulate PPARγ activity at pharmacologically relevant concentrations. Diclofenac acts as a partial agonist and binds to the PPARγ ligand binding pocket (LBP) in typical partial agonist mode, near the β-sheets and helix 3. By contrast, two copies of indomethacin and sulindac sulfide bind the LBP and, in aggregate, these ligands engage in LBP contacts that resemble agonists. Accordingly, both compounds, and ibuprofen, act as strong partial agonists. Assessment of NSAID activities in PPARγ-dependent 3T3-L1 cells reveals that NSAIDs display adipogenic activities and exclusively regulate PPARγ-dependent target genes in a manner that is consistent with their observed binding modes. Further, PPARγ knockdown eliminates indomethacin activities at selected endogenous genes, confirming receptor-dependence of observed effects. We propose that it is important to consider how individual NSAIDs interact with PPARγ to understand their activities, and that it will be interesting to determine whether high dose NSAID therapies result in PPAR activation.

PubMed: 26445566
DOI: 10.1621/nrs.13004

実験手法

X-RAY DIFFRACTION (2.5 Å)