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Structural analysis reveals TLR7 dynamics underlying antagonism.

<div class='caption-title'>Design strategy of TLR7 antagonists.</div>
<div class='caption-title'>Cryo-EM analyses reveal TLR7 conformational dynamics induced by antagonists.</div>
<div class='caption-title'>Binding mode of antagonist to the TLR7 open-form structure.</div>
Tojo S, Zhang Z, Matsui H, Tahara M, Ikeguchi M, Kochi M, Kamada M, Shigematsu H, Tsutsumi A, Adachi N, Shibata T, Yamamoto M, Kikkawa M, Senda T, Isobe Y, Ohto U, Shimizu T
OpenAccess logo Nat Commun 11 5204 (2020)
Related entries: 6lvx, 6lvy, 6lvz, 6lw0

Cited: 29 times
EuropePMC logo PMID: 33060576

Abstract

Toll-like receptor 7 (TLR7) recognizes both microbial and endogenous RNAs and nucleosides. Aberrant activation of TLR7 has been implicated in several autoimmune diseases including systemic lupus erythematosus (SLE). Here, by modifying potent TLR7 agonists, we develop a series of TLR7-specific antagonists as promising therapeutic agents for SLE. These compounds protect mice against lethal autoimmunity. Combining crystallography and cryo-electron microscopy, we identify the open conformation of the receptor and reveal the structural equilibrium between open and closed conformations that underlies TLR7 antagonism, as well as the detailed mechanism by which TLR7-specific antagonists bind to their binding pocket in TLR7. Our work provides small-molecule TLR7-specific antagonists and suggests the TLR7-targeting strategy for treating autoimmune diseases.

Reviews - 6lw1 mentioned but not cited (5)

  1. Structural and functional understanding of the toll-like receptors. Asami J, Shimizu T. Protein Sci 30 761-772 (2021)
  2. 50 Years of structural immunology. Wilson IA, Stanfield RL. J Biol Chem 296 100745 (2021)
  3. Cryo-electron Microscopic Analysis of Single-Pass Transmembrane Receptors. Cai K, Zhang X, Bai XC. Chem Rev 122 13952-13988 (2022)
  4. Host-pathogen protein-nucleic acid interactions: A comprehensive review. Jain A, Mittal S, Tripathi LP, Nussinov R, Ahmad S. Comput Struct Biotechnol J 20 4415-4436 (2022)
  5. Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases. Yadav P, Chakraborty P, Jha NK, Dewanjee S, Jha AK, Panda SP, Mishra PC, Dey A, Jha SK. Viruses 14 2686 (2022)

Articles - 6lw1 mentioned but not cited (1)

  1. Propofol directly binds to and inhibits TLR7. Koutsogiannaki S, Bu W, Maisat W, Manzor M, Zhang Z, Ohto U, Eckenhoff RG, Yuki K. FASEB J 36 e22481 (2022)


Reviews citing this publication (9)

  1. From influenza to COVID-19: Lipid nanoparticle mRNA vaccines at the frontiers of infectious diseases. Pilkington EH, Suys EJA, Trevaskis NL, Wheatley AK, Zukancic D, Algarni A, Al-Wassiti H, Davis TP, Pouton CW, Kent SJ, Truong NP. Acta Biomater 131 16-40 (2021)
  2. Toll-like receptor (TLRs) agonists and antagonists for COVID-19 treatments. Liu ZM, Yang MH, Yu K, Lian ZX, Deng SL. Front Pharmacol 13 989664 (2022)
  3. Nucleic Acid Sensing by Toll-Like Receptors in the Endosomal Compartment. Miyake K, Shibata T, Fukui R, Sato R, Saitoh SI, Murakami Y. Front Immunol 13 941931 (2022)
  4. Potential value of pharmacological agents acting on toll-like receptor (TLR) 7 and/or TLR8 in COVID-19. Khalifa AE, Ghoneim AI. Curr Res Pharmacol Drug Discov 2 100068 (2021)
  5. Recent Advances on Small-Molecule Antagonists Targeting TLR7. Zheng H, Wu P, Bonnet PA. Molecules 28 634 (2023)
  6. Human and Murine Toll-like Receptor-Driven Disease in Systemic Lupus Erythematosus. von Hofsten S, Fenton KA, Pedersen HL. Int J Mol Sci 25 5351 (2024)
  7. Small molecule modulators of immune pattern recognition receptors. Tsukidate T, Hespen CW, Hang HC. RSC Chem Biol 4 1014-1036 (2023)
  8. TLR7 and IgM: Dangerous Partners in Autoimmunity. Amendt T, Yu P. Antibodies (Basel) 12 4 (2023)
  9. Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm. Mahmoud IS, Jarrar YB, Febrimarsa. Clin Exp Med 23 2909-2923 (2023)

Articles citing this publication (14)

  1. Anti-TLR7 Antibody Protects Against Lupus Nephritis in NZBWF1 Mice by Targeting B Cells and Patrolling Monocytes. Murakami Y, Fukui R, Tanaka R, Motoi Y, Kanno A, Sato R, Yamaguchi K, Amano H, Furukawa Y, Suzuki H, Suzuki Y, Tamura N, Yamashita N, Miyake K. Front Immunol 12 777197 (2021)
  2. Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia. Wallach T, Raden M, Hinkelmann L, Brehm M, Rabsch D, Weidling H, Krüger C, Kettenmann H, Backofen R, Lehnardt S. Front Immunol 13 1066456 (2022)
  3. Molecular dynamics simulations reveal the selectivity mechanism of structurally similar agonists to TLR7 and TLR8. Wang X, Chen Y, Zhang S, Deng JN. PLoS One 17 e0260565 (2022)
  4. Identification of Potential Therapeutic Target Genes in Osteoarthritis. Hu Y, Wu Y, Gan F, Jiang M, Chen D, Xie M, Jike Y, Bo Z. Evid Based Complement Alternat Med 2022 8027987 (2022)
  5. TLR7/8 stress response drives histiocytosis in SLC29A3 disorders. Shibata T, Sato R, Taoka M, Saitoh SI, Komine M, Yamaguchi K, Goyama S, Motoi Y, Kitaura J, Izawa K, Yamauchi Y, Tsukamoto Y, Ichinohe T, Fujita E, Hiranuma R, Fukui R, Furukawa Y, Kitamura T, Takai T, Tojo A, Ohtsuki M, Ohto U, Shimizu T, Ozawa M, Yoshida N, Isobe T, Latz E, Mukai K, Taguchi T, Hemmi H, Akira S, Miyake K. J Exp Med 220 e20230054 (2023)
  6. Discovery of new TLR7 agonists by a combination of statistical learning-based QSAR, virtual screening, and molecular dynamics. Abiri A, Rezaei M, Zeighami MH, Vaezpour Y, Dehghan L, KhorramGhahfarokhi M. Inform Med Unlocked 27 100787 (2021)
  7. Identification of the potential TLR7 antagonists by virtual screening and experimental validation. Ruan P, Wang S, Yi P, Yang M, Chen Y, Yang M. Mol Divers 28 1335-1346 (2024)
  8. Structure-Based Optimization of a Fragment-like TLR8 Binding Screening Hit to an In Vivo Efficacious TLR7/8 Antagonist. Betschart C, Faller M, Zink F, Hemmig R, Blank J, Vangrevelinghe E, Bourrel M, Glatthar R, Behnke D, Barker K, Heizmann A, Angst D, Nimsgern P, Jacquier S, Junt T, Zipfel G, Ruzzante G, Loetscher P, Limonta S, Hawtin S, Andre CB, Boulay T, Feifel R, Knoepfel T. ACS Med Chem Lett 13 658-664 (2022)
  9. Targeting TLR Signaling Cascades in Systemic Lupus Erythematosus and Rheumatoid Arthritis: An Update. Kalliolias GD, Basdra EK, Papavassiliou AG. Biomedicines 12 138 (2024)
  10. Decreased TLR7 expression was associated with airway eosinophilic inflammation and lung function in asthma: evidence from machine learning approaches and experimental validation. Yan K, Liang Y. Eur J Med Res 29 116 (2024)
  11. Discovery and properties of a monoclonal antibody targeting 8-oxoA, an oxidized adenine lesion in DNA and RNA. Tew DJ, Hebert JM, Schmier BJ. Redox Biol 62 102658 (2023)
  12. Endosomal Toll-Like Receptors as Therapeutic Targets for Autoimmune Diseases. Miyake K, Shibata T, Fukui R, Murakami Y, Sato R, Hiranuma R. Adv Exp Med Biol 1444 97-108 (2024)
  13. Immunostaining patterns reveal potential morphogenetic role of Toll-like receptors 4 and 7 in the development of mouse respiratory system, liver and pancreas. Sommariva M, Busnelli M, Menegola E, Renzo FD, Indino S, Menon A, Barajon I, Arnaboldi F. Anat Cell Biol 56 228-235 (2023)
  14. Multi-epitope peptide vaccines targeting dengue virus serotype 2 created via immunoinformatic analysis. Morgan RN, Ismail NSM, Alshahrani MY, Aboshanab KM. Sci Rep 14 17645 (2024)


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