ArticleScience signaling2019
Noncompetitive inhibitors of TNFR1 probe conformational activation states.
Article in Science signaling, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
What it found
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Who cites it
34 citing papers in PubMed.
- Article
- TNF as a mediator of metabolic inflammation and body-brain interaction in obesity-driven neuroinflammation and neurodegeneration.Ageing research reviews · 2025Review
- The structural basis for the selective antagonism of soluble TNF-alpha by shark variable new antigen receptors.Nature communications · 2025Article
- Multiplexed Dark FRET Biosensors: An accessible live-cell platform for target- and cell-specific monitoring of protein-protein interactions in 2D and 3D model systems.Research square · 2025Article
- Exploring TNFR1: from discovery to targeted therapy development.Journal of translational medicine · 2025Review
- TLR2 or TLR4 Stimulation Induces Transmembrane TNF-Driven Priming in Macrophages Which Results in Improved Clearance of a Subsequent Staphylococcus aureus Infection.Journal of innate immunity · 2025Article
- Targeting the inter-monomeric space of TNFR1 pre-ligand dimers: A novel binding pocket for allosteric modulators.Computational and structural biotechnology journal · 2025Article
- Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer.Nature reviews. Drug discovery · 2024Review
- Peptide-based allosteric inhibitor targets TNFR1 conformationally active region and disables receptor-ligand signaling complex.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering †.Cancer biology & therapy · 2023Article
- Dual-targeting inhibition of TNFR1 for alleviating rheumatoid arthritis by a novel composite nucleic acid nanodrug.International journal of pharmaceutics: X · 2023Article
- TNF and TNF receptors as therapeutic targets for rheumatic diseases and beyond.Nature reviews. Rheumatology · 2023Review
- How does the same ligand activate signaling of different receptors in TNFR superfamily: a computational study.Journal of cell communication and signaling · 2023Article
- Fluorescence lifetime FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators.Scientific reports · 2023Article
- Zafirlukast Is a Promising Scaffold for Selectively Inhibiting TNFR1 Signaling.ACS bio & med chem Au · 2023Article
- Discovery of a Non-competitive TNFR1 Antagonist Affibody with Picomolar Monovalent Potency That Does Not Affect TNFR2 Function.Molecular pharmaceutics · 2023Article
- FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators.Research square · 2023Article
- Application of polymersomes in membrane protein study and drug discovery: Progress, strategies, and perspectives.Bioengineering & translational medicine · 2023Review
- Indirubin Inhibits TRAIL-Induced Activation of Death Receptor 5 in Jurkat Cells.Natural product communications · 2023Article
- The Screening of Therapeutic Peptides for Anti-Inflammation through Phage Display Technology.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Tumor necrosis factor receptor 1 (TNFR1) is a central mediator of the inflammatory pathway and is associated with several autoimmune diseases such as rheumatoid arthritis. A revision to the canonical model of TNFR1 activation suggests that activation involves conformational rearrangements of preassembled receptor dimers. Here, we identified small-molecule allosteric inhibitors of TNFR1 activation and probed receptor dimerization and function. Specifically, we used a fluorescence lifetime-based high-throughput screen and biochemical, biophysical, and cellular assays to identify small molecules that noncompetitively inhibited the receptor without reducing ligand affinity or disrupting receptor dimerization. We also found that residues in the ligand-binding loop that are critical to the dynamic coupling between the extracellular and the transmembrane domains played a key gatekeeper role in the conformational dynamics associated with signal propagation. Last, using a simple structure-activity relationship analysis, we demonstrated that these newly found molecules could be further optimized for improved potency and specificity. Together, these data solidify and deepen the new model for TNFR1 activation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.