8FKF
Crystal structure of PPARgamma ligand-binding domain in complex with N-CoR peptide and inverse agonist SR36706
Summary for 8FKF
| Entry DOI | 10.2210/pdb8fkf/pdb |
| Descriptor | Peroxisome proliferator-activated receptor gamma, Nuclear receptor corepressor 1, 2-chloro-N-(5-fluoropyridin-3-yl)-5-nitrobenzamide, ... (6 entities in total) |
| Functional Keywords | nuclear receptors, tzds, drug design, therapeutic targets, transcription, transcription-agonist complex |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 34651.42 |
| Authors | MacTavish, B.S.,Kojetin, D.J. (deposition date: 2022-12-21, release date: 2024-04-17, Last modification date: 2025-04-30) |
| Primary citation | MacTavish, B.S.,Zhu, D.,Shang, J.,Shao, Q.,He, Y.,Yang, Z.J.,Kamenecka, T.M.,Kojetin, D.J. Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states. Nat Commun, 16:2065-2065, 2025 Cited by PubMed Abstract: Nuclear receptors (NRs) are thought to dynamically alternate between transcriptionally active and repressive conformations, which are stabilized upon ligand binding. Most NR ligand series exhibit limited bias, primarily consisting of transcriptionally active agonists or neutral antagonists, but not repressive inverse agonists-a limitation that restricts understanding of the functional NR conformational ensemble. Here, we report a NR ligand series for peroxisome proliferator-activated receptor gamma (PPARγ) that spans a pharmacological spectrum from repression (inverse agonism) to activation (agonism) where subtle structural modifications switch compound activity. While crystal structures provide snapshots of the fully repressive state, NMR spectroscopy and conformation-activity relationship analysis reveals that compounds within the series shift the PPARγ conformational ensemble between transcriptionally active and repressive conformations that are natively populated in the apo/ligand-free ensemble. Our findings reveal a molecular framework for minimal chemical modifications that enhance PPARγ inverse agonism and elucidate their influence on the dynamic PPARγ conformational ensemble. PubMed: 40021712DOI: 10.1038/s41467-025-57325-4 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.82 Å) |
Structure validation
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