8ZFO
Crystal Structure of Human PPARgamma Ligand Binding Domain in Complex with GW9662 and nTZDpa
Summary for 8ZFO
| Entry DOI | 10.2210/pdb8zfo/pdb |
| Descriptor | Peroxisome proliferator-activated receptor gamma, 5-CHLORO-1-(4-CHLOROBENZYL)-3-(PHENYLTHIO)-1H-INDOLE-2-CARBOXYLIC ACID, 2-chloro-5-nitro-N-phenylbenzamide, ... (4 entities in total) |
| Functional Keywords | nuclear receptors, tzds, drug design, therapeutic targets, transcription |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 64032.38 |
| Authors | Shang, J.,Kojetin, D.J. (deposition date: 2024-05-08, release date: 2024-08-07, Last modification date: 2025-04-23) |
| Primary citation | Shang, J.,Kojetin, D.J. Unanticipated mechanisms of covalent inhibitor and synthetic ligand cobinding to PPAR gamma. Elife, 13:-, 2024 Cited by PubMed Abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates gene expression programs in response to ligand binding. Endogenous and synthetic ligands, including covalent antagonist inhibitors GW9662 and T0070907, are thought to compete for the orthosteric pocket in the ligand-binding domain (LBD). However, we previously showed that synthetic PPARγ ligands can cooperatively cobind with and reposition a bound endogenous orthosteric ligand to an alternate site, synergistically regulating PPARγ structure and function (Shang et al., 2018). Here, we reveal the structural mechanism of cobinding between a synthetic covalent antagonist inhibitor with other synthetic ligands. Biochemical and NMR data show that covalent inhibitors weaken-but do not prevent-the binding of other ligands via an allosteric mechanism, rather than direct ligand clashing, by shifting the LBD ensemble toward a transcriptionally repressive conformation, which structurally clashes with orthosteric ligand binding. Crystal structures reveal different cobinding mechanisms including alternate site binding to unexpectedly adopting an orthosteric binding mode by altering the covalent inhibitor binding pose. Our findings highlight the significant flexibility of the PPARγ orthosteric pocket, its ability to accommodate multiple ligands, and demonstrate that GW9662 and T0070907 should not be used as chemical tools to inhibit ligand binding to PPARγ. PubMed: 39556436DOI: 10.7554/eLife.99782 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.15 Å) |
Structure validation
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