9r6k | pdb_00009r6k
Crystal structure of PPARgamma in complex with the bisphenol derivative BPPH
Structural highlights
DiseasePPARG_HUMAN Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:601665. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.[1] Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:604367. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.[2] [3] Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:137800. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility. FunctionPPARG_HUMAN Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.[4] [5] [6] Publication Abstract from PubMedThe 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 (PPARgamma), 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 PPARgamma and their adipogenic potential. Using a PPARgamma 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 PPARgamma (BMD20 (muM): 0.23 and 0.34 respectively). Both significantly induced adipogenesis and a positive correlation was found between PPARgamma 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. Mechanistic Insights of BPA Alternatives on PPARgamma Binding and the Consequence on Adipocyte Differentiation.,Flores Gomez D, Korpel N, Grimaldi M, Carivenc C, Balaguer P, Bourguet W, Kamstra JH Environ Sci Technol. 2026 Feb 17;60(6):4526-4539. doi: 10.1021/acs.est.5c07043. , Epub 2026 Feb 6. PMID:41650247[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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