8CPI

Crystal structure of PPAR gamma (PPARG) in complex with WY-14643

Summary for 8CPI

• Entry DOI: 10.2210/pdb8cpi/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 2-({4-CHLORO-6-[(2,3-DIMETHYLPHENYL)AMINO]PYRIMIDIN-2-YL}SULFANYL)ACETIC ACID (3 entities in total)
• Functional Keywords: pparg, allosteric inhibitor, orthosteric inhibitor, structural genomics, structural genomics consortium, sgc, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32315.39

Authors

Chaikuad, A.,Merk, D.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2023-03-02, release date: 2023-07-12, Last modification date: 2024-06-19)

Primary citation

Arifi, S.,Marschner, J.A.,Pollinger, J.,Isigkeit, L.,Heitel, P.,Kaiser, A.,Obeser, L.,Hofner, G.,Proschak, E.,Knapp, S.,Chaikuad, A.,Heering, J.,Merk, D.
Targeting the Alternative Vitamin E Metabolite Binding Site Enables Noncanonical PPAR gamma Modulation.
J.Am.Chem.Soc., 145:14802-14810, 2023

PubMed Abstract: The lipid-sensing transcription factor PPARγ is the target of antidiabetic thiazolidinediones (TZD). At two sites within its ligand binding domain, it also binds oxidized vitamin E metabolites and the vitamin E mimetic garcinoic acid. While the canonical interaction within the TZD binding site mediates classical PPARγ activation, the effects of the second binding on PPARγ activity remain elusive. Here, we identified an agonist mimicking dual binding of vitamin E metabolites and developed a selective ligand of the second site, unveiling potential noncanonical regulation of PPARγ activities. We found that this alternative binding event can simultaneously occur with orthosteric ligands and it exerted different effects on PPARγ-cofactor interactions compared to both orthosteric PPARγ agonists and antagonists, indicating the diverse roles of the two binding sites. Alternative site binding lacked the pro-adipogenic effect of TZD and mediated no classical PPAR signaling in differential gene expression analysis but markedly diminished FOXO signaling, suggesting potential therapeutic applications.

PubMed: 37385602
DOI: 10.1021/jacs.3c03417

Experimental method

X-RAY DIFFRACTION (2.1 Å)