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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}mol.f.u-tokyo.ac.jp


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