9R6K

Crystal structure of PPARgamma in complex with the bisphenol derivative BPPH

This is a non-PDB format compatible entry.

Summary for 9R6K

• Entry DOI: 10.2210/pdb9r6k/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 4-[2-(4-oxidanyl-3-phenyl-phenyl)propan-2-yl]-2-phenyl-phenol (3 entities in total)
• Functional Keywords: nuclear receptor, peroxisome proliferator-activated receptor gamma, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32243.47

Authors

Carivenc, C.,Bourguet, W. (deposition date: 2025-05-12, release date: 2026-02-18, Last modification date: 2026-02-25)

Primary citation

Flores Gomez, D.,Korpel, N.,Grimaldi, M.,Carivenc, C.,Balaguer, P.,Bourguet, W.,Kamstra, J.H.
Mechanistic Insights of BPA Alternatives on PPAR gamma Binding and the Consequence on Adipocyte Differentiation.
Environ Sci Technol., 60:4526-4539, 2026

PubMed Abstract: The obesity epidemic is increasingly linked to environmental factors like endocrine disrupting chemicals (EDCs). Bisphenol A (BPA), a known EDC, has been suspected to be linked to adiposity through activation of peroxisome proliferator activated receptor gamma (PPARγ), a key regulator of adipogenesis. Though many BPA alternatives have been introduced as substitutes, their effects on metabolic health remain unclear. This study aimed to investigate the mechanistic interactions of 11 BPA alternatives with PPARγ and their adipogenic potential. Using a PPARγ reporter assay, we assessed the binding affinity and activation potential of BPA alternatives, followed by X-ray crystallography of two potent activators, 4-benzyloxyphenyl 4-hydroxyphenyl sulfone (BPS4BE) and bisphenol PH (BPPH). Additionally, adipogenesis was assessed via a human mesenchymal stem cells (hMSCs) differentiation assay. Results revealed that the alternatives BPPH and BPS4BE potently activated PPARγ (BMD20 (μM): 0.23 and 0.34 respectively). Both significantly induced adipogenesis and a positive correlation was found between PPARγ activation and adipogenic differentiation. Crystallography revealed distinct binding modes for BPPH and BPS4BE compared to rosiglitazone, indicating partial agonism. These findings raise significant concerns about the safety of BPA alternatives and underscore the need for structure-based risk assessment to ensure safer substitutes.

PubMed: 41650247
DOI: 10.1021/acs.est.5c07043

Experimental method

X-RAY DIFFRACTION (2.3 Å)