API

Stressor: 151

Title

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GW6471

Stressor Overview

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AOPs Including This Stressor

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Events Including This Stressor

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Chemical Table

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AOP Evidence

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Antagonist binding to PPARα leading to body-weight loss

GW6471 - Specifically designed molecules such as the PPARα antagonists GW6471 can bind to PPARα selectively recruiting binding of co-repressors to the PPARα nuclear signaling complex (Xu et al 2002).




Event Evidence

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Binding as antagonist, Antagonist binding to PPARalpha ligand binding domain

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). 



Binding of antagonist, PPAR alpha

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



stabilization, PPAR alpha co-repressor

There is no evidence text for this event.




Stressor Info

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Chemical/Category Description

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GW6471 is a pharmaceutical developed for human diabetes research.  GW6471 was designed specifically to inhibit PPAR alpha signaling (Xu et al 2002).



Characterization of Exposure

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GW6471 was administered in biochemical and cell-free assays (Xu et al 2002).



References

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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.