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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)



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)



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