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

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Science  22 Mar 2013:
Vol. 339, Issue 6126, pp. 1426-1429
DOI: 10.1126/science.1229159

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Dissecting TLR8 Interactions

Toll-like receptors (TLRs) activate the innate immune system in response to invading pathogens. TLR7 and TLR8 recognize single-stranded RNA from viruses and also contribute to the pathogenesis of autoimmune diseases. Tanji et al. (p. 1426) now report the crystal structure of the unliganded TLR8 ectodomain and the TLR8 ectodomain bound to three different small-molecule agonists. Ligand binding to preformed TLR8 dimers induced conformational changes that brought the C-terminal domains closer together, presumably initiating downstream signaling.


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.

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