Noncompetitive inhibitors of TNFR1 probe conformational activation states

Science Signaling
Chih Hung LoJonathan N Sachs

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.

References

Feb 1, 1992·The Journal of Experimental Medicine·D AderkaD Wallach
Jun 2, 1995·The Journal of Biological Chemistry·J H NaismithS R Sprang
Aug 28, 1998·Science·A Ashkenazi, V M Dixit
Jun 6, 2000·Journal of Biomolecular Screening·J H ZhangK R Oldenburg
Oct 11, 2001·Proceedings of the National Academy of Sciences of the United States of America·P H CarterJ A Muckelbauer
Nov 28, 2001·Neurology·N L Sicotte, R R Voskuhl
Apr 13, 2005·Biochemical and Biophysical Research Communications·Hyun-Wook LeeYong-Sung Kim
Jul 27, 2005·Proceedings of the National Academy of Sciences of the United States of America·Ramachandran MuraliMark I Greene
Dec 14, 2007·Nature·James A Wells, Christopher L McClendon
Aug 1, 2009·Nature Methods·Amanda BirminghamCaroline E Shamu
Sep 21, 2010·Molecular & Cellular Proteomics : MCP·Carlos R ReisRobbert H Cool
Nov 18, 2010·Science Signaling·Yohei MukaiYasuo Tsutsumi
Jan 15, 2011·The FEBS Journal·Harald Wajant, Peter Scheurich
Feb 4, 2011·Chemical Biology & Drug Design·Arne SchönErnesto Freire
Aug 3, 2011·Future Medicinal Chemistry·Arne SchönErnesto Freire
Jan 24, 2012·Journal of the American Society of Nephrology : JASN·Tomohito GohdaAndrzej S Krolewski
Apr 13, 2012·The Journal of Biological Chemistry·Christopher C ValleyJonathan N Sachs
Aug 4, 2012·The Journal of Biological Chemistry·Christopher C ValleyJonathan N Sachs
Oct 24, 2012·Biochemistry·Eric S DayAdrian Whitty
Aug 2, 2013·Nature Reviews. Drug Discovery·Denise WoottenPatrick M Sexton
Sep 17, 2013·Autoimmunity Reviews·Evripidis KaltsonoudisAlexandros A Drosos
Oct 1, 2013·Journal of Managed Care Pharmacy : JMCP·Vernon F SchabertDavid J Harrison
Jan 18, 2014·Journal of Biomolecular Screening·Simon J GruberDavid D Thomas
Aug 30, 2014·Cytokine & Growth Factor Reviews·Lisa M Sedger, Michael F McDermott
Dec 30, 2014·The Journal of Biological Chemistry·Sophie SteelandClaude Libert
Jan 28, 2015·Archives of Medical Science : AMS·Krzysztof LisEwa Bałkowiec-Iskra
May 27, 2015·Nature Reviews. Immunology·Dirk BrennerTak W Mak
Dec 15, 2015·Nature Reviews. Rheumatology·George D Kalliolias, Lionel B Ivashkiv
Jan 21, 2016·Science Signaling·Agnieszka MamińskaMarta Miaczynska

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Citations

Oct 28, 2019·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Chih Hung LoJonathan N Sachs
Jan 22, 2020·Protein Science : a Publication of the Protein Society·Chih Hung LoJonathan N Sachs
Jun 13, 2020·Frontiers in Cell and Developmental Biology·Roman FischerKlaus Pfizenmaier
Apr 12, 2021·The Journal of Biological Chemistry·Robyn T RebbeckAdam W Avery
Apr 20, 2021·Computational and Structural Biotechnology Journal·Zhaoqian SuYinghao Wu
Jun 3, 2021·International Journal of Molecular Sciences·Andy RuizLeslie Chavez-Galan
Jun 20, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Swetha Lankipalli, Udupi A Ramagopal
Jun 30, 2021·NPJ Parkinson's Disease·Anthony R BraunJonathan N Sachs
Sep 18, 2020·Biochemistry·Nagamani VunnamBenjamin J Hackel

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