ArticleProceedings of the National Academy of Sciences of the United States of America2019
Quantitative structural assessment of graded receptor agonism.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- GαMetabolites · 2026Article
- Structural optimization of drug molecules with incrementally trained language models.Nature communications · 2026Article
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- Molecular dynamics analysis of a docking-derived baicalein-PPARγ ligand-binding-domain model suggests a pocket-associated AF-2-anchor-silent ensemble.Frontiers in molecular biosciences · 2026Article
- Structural Basis of PPARγ-Mediated Transcriptional Repression by the Covalent Inverse Agonist FX-909.Journal of medicinal chemistry · 2025Article
- The thiazolidinedione drug troglitazone inhibits Gq signaling through direct binding to the Gq alpha subunit through inhibition of GDP release.Molecular pharmacology · 2025Article
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- Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states.Nature communications · 2025Article
- The flexibility of SABRE, a new quantitative receptor function model, when fitting challenging concentration-effect data.Frontiers in pharmacology · 2025Article
- Antidiabetic potential of thiazolidinedione derivatives with efficient design, molecular docking, structural activity relationship, and biological activity: an update review (2021-2023).Molecular diversity · 2024Review
- Serum biochemical evaluation following administration of imidazolyl thiazolidinedione in streptozotocin-induced diabetic rats.Journal of molecular histology · 2024Article
- Article
- Unanticipated mechanisms of covalent inhibitor and synthetic ligand cobinding to PPARγ.bioRxiv : the preprint server for biology · 2024Article
- Structural Studies on the Binding Mode of Bisphenols to PPARγ.Biomolecules · 2024Article
- Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR.Nature communications · 2024Article
- Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states.bioRxiv : the preprint server for biology · 2024Article
- Nuclear receptor interdomain communication is mediated by the hinge with ligand specificity.bioRxiv : the preprint server for biology · 2024Article
- Combined In Silico and In Vitro Analyses to Assess the Anticancer Potential of Thiazolidinedione-Thiosemicarbazone Hybrid Molecules.International journal of molecular sciences · 2023Article
- Article
- Ligand-induced shifts in conformational ensembles that describe transcriptional activation.eLife · 2022Article
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Authors and funding
5 authors.
Funding
Abstract
Ligand-receptor interactions, which are ubiquitous in physiology, are described by theoretical models of receptor pharmacology. Structural evidence for graded efficacy receptor conformations predicted by receptor theory has been limited but is critical to fully validate theoretical models. We applied quantitative structure-function approaches to characterize the effects of structurally similar and structurally diverse agonists on the conformational ensemble of nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). For all ligands, agonist functional efficacy is correlated to a shift in the conformational ensemble equilibrium from a ground state toward an active state, which is detected by NMR spectroscopy but not observed in crystal structures. For the structurally similar ligands, ligand potency and affinity are also correlated to efficacy and conformation, indicating ligand residence times among related analogs may influence receptor conformation and function. Our results derived from quantitative graded activity-conformation correlations provide experimental evidence and a platform with which to extend and test theoretical models of receptor pharmacology to more accurately describe and predict ligand-dependent receptor activity.
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