API

Event: 998

Key Event Title

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Binding of antagonist, PPAR alpha

Short name

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Binding of antagonist, PPAR alpha

Key Event Component

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Process Object Action
receptor antagonist activity peroxisome proliferator-activated receptor alpha increased

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Antagonist binding to PPARα leading to body-weight loss MolecularInitiatingEvent

Stressors

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Name
GW6471

Level of Biological Organization

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Biological Organization
Molecular

Cell term

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Cell term
eukaryotic cell


Organ term

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Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens Strong NCBI
Saccharomyces cerevisiae Saccharomyces cerevisiae Strong NCBI

Life Stage Applicability

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Life stage Evidence
Not Otherwise Specified

Sex Applicability

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Term Evidence
Unspecific

How This Key Event Works

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Binding of molecules to peroxisome proliferator-activated receptor α (PPARα) can cause either agonistic or antagonistic signaling depending on molecular structure (Xu et al 2001, Xu et al 2002). Certain molecules that can bind to the PPARα ligand binding domain have been observed to cause conformational changes that induce increased affinity to co-repressors which decrease PPARα nuclear signaling (Xu et al 2002). Binding of co-repressors such as the silencing mediator for retinoid and thyroid hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR) to PPARα is reinforced by the antagonist, which blocks the AF-2 helix from adopting the active conformation, as demonstrated in x-ray crystallography results presented in Xu et al (2002). Thus, molecules that bind to PPARα that can enhance co-repressor binding act as PPARα antagonists.


How It Is Measured or Detected

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In Xu et al (2002), X-ray crystallography was used to characterize the suppressed PPARα signaling complex (PPARα / GW6471 / SMRT) and was compared against the activated PPARα complex which included binding of PPARα with the agonist GW409544 and the co-activator, steroid receptor coactivator-1 (SRC-1). For simple PPARα binding assessment, competitive binding assays are availables, however these must be coupled with nuclear signaling activation / inhibition assays to determine if chemicals are agonists or antagonists.


Evidence Supporting Taxonomic Applicability

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The fundamental mechanics for nuclear receptor binding as well as demonstration of co-repressor recruitment have been observed to be conserved when comparing humans and yeast (Nagy et al 1999). PPARα has been cloned from frogs, rats, guinea pigs, and humans where the DNA-binding domain has been shown to be identical across species, however the ligand binding domain has exhibited lower homology, likely adapted to differences in dietary ligands among species (Willson et al 2000). Overall, there is evidence for fairly conserved taxonomic applicability across vertebrates, though care should be given when extrapolating across species.


Evidence for Perturbation by Stressor


Overview for Molecular Initiating Event

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Antagonist binding of GW6471 causing increased stabilization of the co-repressors SMRT and N-CoR to the PPARα ligand binding domain has been explicitly demonstrated through x-ray crystallography (Xu et al 2002).

 



GW6471

Binding to PPAR alpha is implied given observations of inhibited PPAR alpha nuclear signaling inhibition by nitrotoluenes (Wilbanks et al 2014). 


References

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Nagy L, Kao H-Y, Love JD, Li C, Banayo E, Gooch JT, Krishna V, Chatterjee K, Evans RM, Schwabe JWR: Mechanism of corepressor binding and release from nuclear hormone receptors. Genes Dev 1999, 13(24):3209-3216.

Xu HE, Lambert MH, Montana VG, Plunket KD, Moore LB, Collins JL, Oplinger JA, Kliewer SA, Gampe RT, McKee DD et al: Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proceedings of the National Academy of Sciences 2001, 98(24):13919-13924.

Wilbanks, M., Gust, K.A., Atwa, S., Sunesara, I., Johnson, D., Ang, C.Y., Meyer., S.A., and Perkins, E.J. 2014. Validation of a genomics-based hypothetical adverse outcome pathway: 2,4-dinitrotoluene perturbs PPAR signaling thus impairing energy metabolism and exercise endurance. Toxicological Sciences. 141(1):44-58.

Willson TM, Brown PJ, Sternbach DD, Henke BR: The PPARs:  From Orphan Receptors to Drug Discovery. J Med Chem 2000, 43(4):527-550.

Xu HE, Stanley TB, Montana VG, Lambert MH, Shearer BG, Cobb JE, McKee DD, Galardi CM, Plunket KD, Nolte RT et al: Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPAR[alpha]. Nature 2002, 415(6873):813-817.