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Science 339 (6126): 1426-1429

Copyright © 2013 by the American Association for the Advancement of Science

Structural Reorganization of the Toll-Like Receptor 8 Dimer Induced by Agonistic Ligands

Hiromi Tanji,1,3,* Umeharu Ohto,1,3,* Takuma Shibata,2 Kensuke Miyake,2 Toshiyuki Shimizu1,3,{dagger}

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.

1 Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
2 Division of Innate Immunity, Department of Microbiology and Immunology, Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
3 RIKEN SPring-8 Center, Kouto 1-1-1, Sayo, Hyogo 679-5148, Japan.

* These authors contributed equally to this work.

{dagger} Corresponding author. E-mail: shimizu{at}

The Structural Basis for Endotoxin-induced Allosteric Regulation of the Toll-like Receptor 4 (TLR4) Innate Immune Receptor.
T. Paramo, T. J. Piggot, C. E. Bryant, and P. J. Bond (2013)
J. Biol. Chem. 288, 36215-36225
   Abstract »    Full Text »    PDF »
Human TLR8 is activated upon recognition of Borrelia burgdorferi RNA in the phagosome of human monocytes.
J. L. Cervantes, C. J. La Vake, B. Weinerman, S. Luu, C. O'Connell, P. H. Verardi, and J. C. Salazar (2013)
J. Leukoc. Biol. 94, 1231-1241
   Abstract »    Full Text »    PDF »

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