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Structural analysis reveals TLR7 dynamics underlying antagonism

Author

Listed:
  • Shingo Tojo

    (Sumitomo Dainippon Pharma Co., Ltd.)

  • Zhikuan Zhang

    (The University of Tokyo)

  • Hiroyuki Matsui

    (Sumitomo Dainippon Pharma Co., Ltd.)

  • Masahiro Tahara

    (Sumitomo Dainippon Pharma Co., Ltd.)

  • Mitsunori Ikeguchi

    (Graduate School of Medical Life Science, Yokohama City University)

  • Mami Kochi

    (Sumitomo Dainippon Pharma Co., Ltd.)

  • Mami Kamada

    (Sumitomo Dainippon Pharma Co., Ltd.)

  • Hideki Shigematsu

    (RIKEN SPring-8 Center)

  • Akihisa Tsutsumi

    (Graduate School of Medicine, the University of Tokyo)

  • Naruhiko Adachi

    (High Energy Accelerator Research Organization (KEK))

  • Takuma Shibata

    (The University of Tokyo)

  • Masaki Yamamoto

    (RIKEN SPring-8 Center)

  • Masahide Kikkawa

    (Graduate School of Medicine, the University of Tokyo)

  • Toshiya Senda

    (High Energy Accelerator Research Organization (KEK))

  • Yoshiaki Isobe

    (Sumitomo Dainippon Pharma Co., Ltd.)

  • Umeharu Ohto

    (The University of Tokyo)

  • Toshiyuki Shimizu

    (The University of Tokyo)

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.

Suggested Citation

  • Shingo Tojo & Zhikuan Zhang & Hiroyuki Matsui & Masahiro Tahara & Mitsunori Ikeguchi & Mami Kochi & Mami Kamada & Hideki Shigematsu & Akihisa Tsutsumi & Naruhiko Adachi & Takuma Shibata & Masaki Yamam, 2020. "Structural analysis reveals TLR7 dynamics underlying antagonism," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19025-z
    DOI: 10.1038/s41467-020-19025-z
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