Journal
CELL REPORTS
Volume 25, Issue 12, Pages 3371-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.11.081
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Funding
- Japanese Ministry of Education, Culture, Sports, Science, and Technology [26711002, 16K08827, 16H06388, 16H02494]
- CREST-JST
- Takeda Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Daiichi Sankyo Foundation of Life Science
- Uehara Memorial Foundation
- Naito Foundation
- NIH/NIAID [HSN272200900033C, HHSN272201400056C]
- Japan Agency for Medical Research and Development (AMED) [JP18am0101070]
- Grants-in-Aid for Scientific Research [26711002, 16K08827, 16H02494] Funding Source: KAKEN
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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.
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