Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands
Summary: Toll-like receptor 7 (TLR7) is an innate immune receptor for single-stranded RNA (ssRNA) and has important roles in infectious diseases. We previously reported that TLR7 shows synergistic activation in response to two ligands, guanosine and ssRNA. However, the specific ssRNA sequence prefer...
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doaj-375b181e186041cc9c1479bbedd8b5ba2020-11-24T21:34:58ZengElsevierCell Reports2211-12472018-12-01251233713381.e5Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic LigandsZhikuan Zhang0Umeharu Ohto1Takuma Shibata2Masato Taoka3Yoshio Yamauchi4Ryota Sato5Nikunj M. Shukla6Sunil A. David7Toshiaki Isobe8Kensuke Miyake9Toshiyuki Shimizu10Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanGraduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding authorDivision 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, JapanDepartment of Chemistry, Graduate School of Science and Technology, Tokyo Metropolitan University, Minami-osawa 1-1, Hachioji, Tokyo 192-0397, JapanDepartment of Chemistry, Graduate School of Science and Technology, Tokyo Metropolitan University, Minami-osawa 1-1, Hachioji, Tokyo 192-0397, JapanDivision 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, JapanDepartment of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 2-132 CCRB, 2231 6th Street SE, Minneapolis, MN 55455, USADepartment of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 2-132 CCRB, 2231 6th Street SE, Minneapolis, MN 55455, USADepartment of Chemistry, Graduate School of Science and Technology, Tokyo Metropolitan University, Minami-osawa 1-1, Hachioji, Tokyo 192-0397, JapanDivision 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, JapanGraduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding authorSummary: Toll-like receptor 7 (TLR7) is an innate immune receptor for single-stranded RNA (ssRNA) and has important roles in infectious diseases. We previously reported that TLR7 shows synergistic activation in response to two ligands, guanosine and ssRNA. However, the specific ssRNA sequence preference, detailed recognition mode of TLR7 and its ligand, and molecular determinants of TLR7 and TLR8 selectivity remain unknown. Here, we report on TLR7 from a large-scale crystallographic study combined with a multifaceted approach. We reveal that successive uridine-containing ssRNAs fully or moderately bind TLR7, whereas single uridine-containing ssRNAs have reduced affinities. We also reveal the detailed relationships between the chemical structures of ligands and their binding to TLR7. We demonstrate that an engineered TLR8 mutant alters its responsiveness to TLR7-specific ligands. Finally, we identify guanosine 2′,3′-cyclic phosphate (2′,3′-cGMP) as a possible endogenous ligand for TLR7 with greater affinity than guanosine. The abundant structural information will facilitate future development of treatments targeting TLR7. : Zhang et al. determine a series of crystal structures of TLR7 complexed with agonistic ligands. The findings contain detailed ssRNA sequence specificity, recognition mechanism(s) of synthetic ligands, the molecular basis of TLR7 and TLR8 ligand selectivity, and identification of possible endogenous ligands with a high activity. Keywords: innate immunity, Toll-like receptor, single-stranded RNA, low-molecular-weight agonists, guanosine 2′,3′-cyclic phosphatehttp://www.sciencedirect.com/science/article/pii/S2211124718318722 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zhikuan Zhang Umeharu Ohto Takuma Shibata Masato Taoka Yoshio Yamauchi Ryota Sato Nikunj M. Shukla Sunil A. David Toshiaki Isobe Kensuke Miyake Toshiyuki Shimizu |
spellingShingle |
Zhikuan Zhang Umeharu Ohto Takuma Shibata Masato Taoka Yoshio Yamauchi Ryota Sato Nikunj M. Shukla Sunil A. David Toshiaki Isobe Kensuke Miyake Toshiyuki Shimizu Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands Cell Reports |
author_facet |
Zhikuan Zhang Umeharu Ohto Takuma Shibata Masato Taoka Yoshio Yamauchi Ryota Sato Nikunj M. Shukla Sunil A. David Toshiaki Isobe Kensuke Miyake Toshiyuki Shimizu |
author_sort |
Zhikuan Zhang |
title |
Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands |
title_short |
Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands |
title_full |
Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands |
title_fullStr |
Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands |
title_full_unstemmed |
Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands |
title_sort |
structural analyses of toll-like receptor 7 reveal detailed rna sequence specificity and recognition mechanism of agonistic ligands |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2018-12-01 |
description |
Summary: Toll-like receptor 7 (TLR7) is an innate immune receptor for single-stranded RNA (ssRNA) and has important roles in infectious diseases. We previously reported that TLR7 shows synergistic activation in response to two ligands, guanosine and ssRNA. However, the specific ssRNA sequence preference, detailed recognition mode of TLR7 and its ligand, and molecular determinants of TLR7 and TLR8 selectivity remain unknown. Here, we report on TLR7 from a large-scale crystallographic study combined with a multifaceted approach. We reveal that successive uridine-containing ssRNAs fully or moderately bind TLR7, whereas single uridine-containing ssRNAs have reduced affinities. We also reveal the detailed relationships between the chemical structures of ligands and their binding to TLR7. We demonstrate that an engineered TLR8 mutant alters its responsiveness to TLR7-specific ligands. Finally, we identify guanosine 2′,3′-cyclic phosphate (2′,3′-cGMP) as a possible endogenous ligand for TLR7 with greater affinity than guanosine. The abundant structural information will facilitate future development of treatments targeting TLR7. : Zhang et al. determine a series of crystal structures of TLR7 complexed with agonistic ligands. The findings contain detailed ssRNA sequence specificity, recognition mechanism(s) of synthetic ligands, the molecular basis of TLR7 and TLR8 ligand selectivity, and identification of possible endogenous ligands with a high activity. Keywords: innate immunity, Toll-like receptor, single-stranded RNA, low-molecular-weight agonists, guanosine 2′,3′-cyclic phosphate |
url |
http://www.sciencedirect.com/science/article/pii/S2211124718318722 |
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