ArticleNature communications2025
Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Targeting Nuclear Import of Thyroid Hormone Receptor Alpha with Natural Polyphenols: Potential Mechanism for Lipolysis in Metabolic Dysfunction-Associated Steatotic Liver Disease.Current issues in molecular biology · 2026Article
- Ligand Drift Rate Descriptor in Receptor Pocket: Molecular Docking Sampling for Differentiating Partial Agonists in Nuclear Receptors.Journal of chemical information and modeling · 2026Article
- Molecular Dynamics of PPAR Nuclear Receptors: From Ligand Binding to Transcriptional Regulation.Cells · 2026Review
- From possibility to precision in macromolecular ensemble prediction.Nature methods · 2026Article
- Distinctive Behavior and Selective Modulation of PPARγ by Pentacyclic Triterpenoid Pomolic Acid and Hederagenin fromJournal of agricultural and food chemistry · 2026Article
- Glabridin improves cardiac remodeling after myocardial infarction by activating PPARγ to regulate the ubiquitination and degradation of EGFR.Biology direct · 2026Article
- Structural pharmacology of Chinese medicine: technological breakthroughs in decoding multi-target synergy and precision mechanisms.Advanced biotechnology · 2026Review
- Synthetic Modulators of the Vitamin D Receptor: From Structural Innovation to Disease-Specific Applications.Biomolecules · 2026Review
- Article
- Structural Elucidation and Covalent Modulation of the Autorepressed Orphan Nuclear Receptor NR2F6.ACS chemical biology · 2025Article
- Structural Basis of PPARγ-Mediated Transcriptional Repression by the Covalent Inverse Agonist FX-909.Journal of medicinal chemistry · 2025Article
- Article
- Data mining historical Chinese medical recipe collections and nuclear receptor profiling identify plant fractions that modulate glucocorticoid receptor activity.Frontiers in pharmacology · 2025Article
- Article
- Unanticipated mechanisms of covalent inhibitor and synthetic ligand cobinding to PPARγ.bioRxiv : the preprint server for biology · 2024Article
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8 authors.
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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.
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