ArticleProceedings of the National Academy of Sciences of the United States of America2022
A structural mechanism of nuclear receptor biased agonism.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- RT206 Couples Partial PPARα/γ Agonism with Ligand-Dependent Allosteric Potentiation of FXR Signaling in Liver Cells.Biomolecules · 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
- Article
- Synthetic Modulators of the Vitamin D Receptor: From Structural Innovation to Disease-Specific Applications.Biomolecules · 2026Review
- In search of nonlipogenic ABCA1 inducers (NLAI): precision coregulator TR-FRET identifies diverse signatures for LXR ligands.bioRxiv : the preprint server for biology · 2025Article
- Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states.Nature communications · 2025Article
- Transcription factors in the development and treatment of immune disorders.Transcription · 2025Review
- Agonists of the Nuclear Receptor PPARγ Can Produce Biased Signaling.Molecular pharmacology · 2024Article
- Oxidative Stress and the Nrf2/PPARγ Axis in the Endometrium: Insights into Female Fertility.Cells · 2024Review
- Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets.Signal transduction and targeted therapy · 2024Review
- Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states.bioRxiv : the preprint server for biology · 2024Article
- A unified analysis of evolutionary and population constraint in protein domains highlights structural features and pathogenic sites.Communications biology · 2024Article
- Roles of distinct nuclear receptors in diabetic cardiomyopathy.Frontiers in pharmacology · 2024Review
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- Prenylated Chrysin Derivatives as Partial PPARγ Agonists with Adiponectin Secretion-Inducing Activity.ACS medicinal chemistry letters · 2023Article
- A structural mechanism of nuclear receptor biased agonism.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
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Authors and funding
5 authors.
Funding
Abstract
Efforts to decrease the adverse effects of nuclear receptor (NR) drugs have yielded experimental agonists that produce better outcomes in mice. Some of these agonists have been shown to cause different, not just less intense, on-target transcriptomic effects; however, a structural explanation for such agonist-specific effects remains unknown. Here, we show that partial agonists of the NR peroxisome proliferator-associated receptor γ (PPARγ), which induce better outcomes in mice compared to clinically utilized type II diabetes PPARγ-binding drugs thiazolidinediones (TZDs), also favor a different group of coactivator peptides than the TZDs. We find that PPARγ full agonists can also be biased relative to each other in terms of coactivator peptide binding. We find differences in coactivator-PPARγ bonding between the coactivator subgroups which allow agonists to favor one group of coactivator peptides over another, including differential bonding to a C-terminal residue of helix 4. Analysis of all available NR-coactivator structures indicates that such differential helix 4 bonding persists across other NR-coactivator complexes, providing a general structural mechanism of biased agonism for many NRs. Further work will be necessary to determine if such bias translates into altered coactivator occupancy and physiology in cells.
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