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Structural Studies on the Binding Mode of Bisphenols to PPARγ
Abibe Useini1, Inken Kaja Schwerin2, Georg Künze2,3,4
1Institute of Bioanalytical Chemistry, Centre for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, 04103 Leipzig, Germany.
Biomolecules
|June 27, 2024
Summary
Bisphenol A (BPA) and bisphenol B (BPB) bind to the PPARγ ligand binding domain but do not activate it. Molecular dynamics simulations reveal key interactions influencing their binding modes.
Area of Science:
- Biochemistry
- Molecular Biology
- Toxicology
Background:
- Bisphenol A (BPA) and bisphenol B (BPB) are common plastic additives with potential endocrine-disrupting and metabolic health effects.
- Peroxisome proliferator-activated receptor gamma (PPARγ) is crucial for metabolic regulation and adipogenesis, making it a key target for understanding obesity.
Purpose of the Study:
- To investigate the molecular interactions between PPARγ and BPA/BPB using structural and simulation methods.
- To elucidate the binding mechanisms and potential functional consequences of BPA and BPB binding to PPARγ.
Main Methods:
- X-ray crystallography was used to determine the binding sites of BPA and BPB within the PPARγ ligand binding domain.
- Molecular dynamics (MD) simulations and free energy analyses were employed to study the dynamic interactions and energetic contributions.
Main Results:
- Crystallography confirmed BPA and BPB binding to PPARγ near C285, a site known for interactions with other PPARγ modulators.
- BPA and BPB did not interact with Y437 in the activation function 2 site, indicating they cannot stabilize the active PPARγ conformation.
- MD simulations identified I341 as having a significant energetic contribution to the binding of BPA and BPB.
Conclusions:
- BPA and BPB bind to PPARγ but are unlikely to activate its signaling pathway due to their inability to stabilize the active conformation.
- The binding interactions, particularly involving I341, provide insights into the molecular basis of BPA and BPB's interaction with PPARγ.
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