title: Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands.
abstract: Toll-like receptor 7 (TLR7) and TLR8 recognize single-stranded RNA and initiate innate immune responses. Several synthetic agonists of TLR7-TLR8 display novel therapeutic potential; however, the molecular basis for ligand recognition and activation of signaling by TLR7 or TLR8 is largely unknown. In this study, the crystal structures of unliganded and ligand-induced activated human TLR8 dimers were elucidated. Ligand recognition was mediated by a dimerization interface formed by two protomers. Upon ligand stimulation, the TLR8 dimer was reorganized such that the two C termini were brought into proximity. The loop between leucine-rich repeat 14 (LRR14) and LRR15 was cleaved; however, the N- and C-terminal halves remained associated and contributed to ligand recognition and dimerization. Thus, ligand binding induces reorganization of the TLR8 dimer, which enables downstream signaling processes.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanji
authors.forename: Umeharu
authors.initials: U
authors.lastname: Ohto
authors.forename: Takuma
authors.initials: T
authors.lastname: Shibata
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism
chemical_list: C551788:CL 075; C547051:CL097 compound; D007093:Imidazoles; D008024:Ligands; D050505:Mutant Proteins; D011804:Quinolines; C495349:TLR8 protein, human; D013844:Thiazoles; D051200:Toll-Like Receptor 8; C402365:resiquimod