Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA
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Toll-like receptor 7 (TLR7) is a single-stranded RNA (ssRNA) sensor in innate immunity and also responds to guanosine and chemical ligands, such as imidazoquinoline compounds. However, TLR7 activation mechanism by these ligands remain largely unknown. Here, we generated crystal structures of three TLR7 complexes, and found that all formed an activated m-shaped dimer with two ligand-binding sites. The first site conserved in TLR7 and TLR8 was used for small ligand-binding essential for its activation. The second site spatially distinct from that of TLR8 was used for a ssRNA-binding that enhanced the affinity of the first-site ligands. The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. Our structural, biochemical, and mutagenesis studies indicated that TLR7 is a dual receptor for guanosine and uridine-containing ssRNA. Our findings have important implications for understanding of TLR7 function, as well as for therapeutic manipulation of TLR7 activation.
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The ligands of TLR7 and TLR8 are degradation products of RNA including short stretches of ssRNA and nucleosides.
“Recently, the ligands of TLR7 and TLR8 have been reported as degradation products of RNA including short stretches of ssRNA and nucleosides (Tanji et al. 2015; Zhang et al. 2016).”
From RNA Circularization Diminishes Immunogenicity and Can Extend Translation Duration In Vivo (2019) · cites this paper as Zhang et al. 2016
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- Authors
- Zhang, Z., Ohto, U., Shibata, T., Krayukhina, E., Taoka, M., Yamauchi, Y., Tanji, H., Isobe, T., Uchiyama, S., Miyake, K., & Shimizu, T.
- Affiliations
- The University of Tokyo (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- The University of Osaka (JP)
- Tokyo Metropolitan University (JP)
- National Institutes of Natural Sciences (JP)
- Corresponding author
- Shimizu, Toshiyuki
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 45
- Issue
- 4
- Pages
- 737-748
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2530273804
- Cited by
- 461
- References
- 48
- Citations by year
- 2026: 34 · 2025: 45 · 2024: 57 · 2023: 56 · 2022: 46 · 2021: 66 · 2020: 44 · 2019: 41 · 2018: 43 · 2017: 25 · 2016: 4
- FWCI
- 23.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 382 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Daiichi Sankyo Foundation of Life Science
- Ministry of Education, Culture, Sports, Science and Technology
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TLR7, guanosine, single-stranded RNA, uridine, imidazoquinolines, ligand binding sites, receptor dimerization, innate immunity, crystal structure, TLR8
- MeSH terms
- Animals, Binding Sites, Cell Line, Drosophila, Guanosine, Humans, Immunity, Innate, Ligands, Macaca mulatta, RNA, Toll-Like Receptor 7, HEK293 Cells
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