title: [Structural Analyses of Toll-like Receptor Sensing Single-stranded Nucleic Acids and Its Application].
abstract: Toll-like receptors (TLRs) are a family of pattern-recognition receptors that recognize microbial components and initiate subsequent immune responses. TLR7 and TLR8 recognize single-stranded (ss)RNA and initiate innate immune responses. Moreover, several small-molecule compounds have been identified as TLR7 and TLR8 activators. We determined the crystal structures of unliganded and ligand-induced activated human TLR8 dimers. Upon ligand stimulation, the TLR8 dimer was reorganized such that the two C-termini were brought into proximity. Ligand binding induces reorganization of the TLR8 dimer, which enables downstream signaling processes. To elucidate how TLR8 recognizes its natural ligand, ssRNA, as well as how the receptor can be activated by ssRNA that is structurally and chemically very different from the chemical ligands, we performed crystallographic studies of TLR8 in complex with ssRNA. TLR8 recognizes, at distinct sites, uridine and small oligonucleotides derived from the degradation of ssRNA. Uridine bound the site on the dimerization interface where small chemical ligands are recognized, whereas short oligonucleotides bound a newly identified site. Based on structural information, new compounds have been developed. We describe the crystal structure of a newly developed agonist, C2-butyl furo[2,3-c]quinolone.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000639:trends; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008024:Ligands; D055503:Protein Multimerization; D011804:Quinolines / Q000737:chemistry; D012313:RNA / Q000276:immunology*; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000737:chemistry* / Q000276:immunology*; D051200:Toll-Like Receptor 8 / Q000737:chemistry* / Q000276:immunology*; D014529:Uridine / Q000276:immunology
chemical_list: D008024:Ligands; D011804:Quinolines; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D012313:RNA; D014529:Uridine