Structural analysis reveals TLR7 dynamics underlying antagonism

Shingo Tojo (), Zhikuan Zhang, Hiroyuki Matsui, Masahiro Tahara, Mitsunori Ikeguchi, Mami Kochi, Mami Kamada, Hideki Shigematsu, Akihisa Tsutsumi, Naruhiko Adachi, Takuma Shibata, Masaki Yamamoto, Masahide Kikkawa, Toshiya Senda, Yoshiaki Isobe, Umeharu Ohto () and Toshiyuki Shimizu ()
Additional contact information
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

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19025-z

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