title: Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Zhikuan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Umeharu
authors.initials: U
authors.lastname: Ohto
authors.affiliation: Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Elena
authors.initials: E
authors.lastname: Krayukhina
authors.affiliation: Department of Chemistry, Graduate School of Science and Technology, Tokyo Metropolitan University, Minami-osawa 1-1, Hachioji, Tokyo 192-0397, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Taoka
authors.affiliation: Department of Chemistry, Graduate School of Science and Technology, Tokyo Metropolitan University, Minami-osawa 1-1, Hachioji, Tokyo 192-0397, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamauchi
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanji
authors.affiliation: Department of Chemistry, Graduate School of Science and Technology, Tokyo Metropolitan University, Minami-osawa 1-1, Hachioji, Tokyo 192-0397, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Isobe
authors.affiliation: Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Japan; Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Uchiyama
authors.affiliation: Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: shimizu@mol.f.u-tokyo.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000276:immunology; D002460:Cell Line; D004330:Drosophila; D006151:Guanosine / Q000276:immunology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008024:Ligands; D008253:Macaca mulatta; D012313:RNA / Q000276:immunology / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*
chemical_list: D008024:Ligands; D051199:Toll-Like Receptor 7; D006151:Guanosine; D012313:RNA
keywords: Toll-like receptor 7; X-ray crystallography; guanosine innate immunity; pattern-recognition receptor; single-stranded RNA; synergistic effect