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PDBsum entry 4xta
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Transcription
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PDB id
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4xta
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References listed in PDB file
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Key reference
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Title
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Mechanisms of peroxisome proliferator activated receptor γ regulation by non-Steroidal anti-Inflammatory drugs.
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Authors
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A.C.Puhl,
F.A.Milton,
A.Cvoro,
D.H.Sieglaff,
J.C.Campos,
A.Bernardes,
C.S.Filgueira,
J.L.Lindemann,
T.Deng,
F.A.Neves,
I.Polikarpov,
P.Webb.
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Ref.
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Nucl Recept Signal, 2015,
13,
e004.
[DOI no: ]
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PubMed id
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Abstract
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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.
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