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Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds
Shusaku Harada1, Youhei Hiromori2, Shota Nakamura3
1Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Scientific Reports
|February 18, 2015
Summary
Triphenyltin (TPT) and tributyltin (TBT) disrupt endocrine function via PPARγ. Structural analysis reveals TPT strongly activates PPARγ through unique π-π interactions, elucidating its potent endocrine-disrupting mechanism.
Area of Science:
- Endocrinology
- Toxicology
- Structural Biology
Background:
- Organotin compounds (TPT, TBT) are endocrine disruptors.
- They target the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway.
- TPT is a particularly potent PPARγ agonist.
Purpose of the Study:
- Elucidate the mechanism of organotin-induced PPARγ activation.
- Analyze structural interactions between PPARγ ligand-binding domain (LBD) and TPT/TBT.
- Determine the structural basis for TPT's strong PPARγ agonistic activity.
Main Methods:
- X-ray crystallography to determine complex structures.
- Mass spectroscopy for interaction analysis.
- Cell-based activity assays for functional validation.
Main Results:
- Crystal structures of PPARγ-LBD/TBT and PPARγ-LBD/TPT complexes determined at high resolution (1.95 Å and 1.89 Å).
- Organotin binding involves non-covalent ionic interactions between Cys285 sulfur and the tin atom.
- TPT's enhanced activity is attributed to π-π interactions with PPARγ LBD helix 12.
Conclusions:
- Structural insights into organotin binding and PPARγ activation.
- Elucidation of the specific interactions driving TPT's potent PPARγ agonism.
- Provides a foundation for understanding and potentially mitigating organotin endocrine disruption.
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