4XUH

PPARgamma ligand binding domain in complex with sulindac sulfide

Summary for 4XUH

• Entry DOI: 10.2210/pdb4xuh/pdb
• Related: 3SZ1 4XTA
• Descriptor: Peroxisome proliferator-activated receptor gamma, 2-[(3Z)-6-fluoranyl-2-methyl-3-[(4-methylsulfanylphenyl)methylidene]inden-1-yl]ethanoic acid (3 entities in total)
• Functional Keywords: nuclear receptor, ppargamma, sulindac sulfide, nsaids, translation
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 2
• Total formula weight: 64831.37

Authors

Puhl, A.C.,Polikaporv, I.,Webb, P. (deposition date: 2015-01-25, release date: 2016-07-27, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.22 Å)