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Key Event Title
Binding of antagonist, PPAR alpha
|Level of Biological Organization|
Key Event Components
|receptor antagonist activity||peroxisome proliferator-activated receptor alpha||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|PPARα antagonism leading to body-weight loss||MolecularInitiatingEvent||Kurt A. Gust (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Not Otherwise Specified|
Key Event Description
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
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.
Domain of Applicability
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.
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.