Abstract
Toll-like receptors (TLRs) play a central role in the innate immune response by recognizing conserved structural patterns in a variety of microbes. TLRs are classified into six families, of which TLR7 family members include TLR7, 8, and 9, which are localized to endolysosomal compartments recognizing viral infection in the form of foreign nucleic acids. In our current study, we focused on TLR8, which has been shown to recognize different types of ligands such as viral or bacterial ssRNA as well as small synthetic molecules. The primary sequences of rodent and non-rodent TLR8s are similar, but the antiviral compound (R848) that activates the TLR8 pathway is species-specific. Moreover, the factors underlying the receptor's species-specificity remain unknown. To this end, comparative homology modeling, molecular dynamics simulations refinement, automated docking and computational mutagenesis studies were employed to probe the intermolecular interactions between this anti-viral compound and TLR8. Furthermore, comparative analyses of modeled TLR8 (rodent and non-rodent) structures have shown that the variation mainly occurs at LRR14-15 (undefined region); hence, we hypothesized that this variation may be the primary reason for the exhibited species-specificity. Our hypothesis was further bolstered by our docking studies, which clearly showed that this undefined region was in close proximity to the ligand-binding site and thus may play a key role in ligand recognition. In addition, the interface between the ligand and TLR8s varied depending upon the amino acid charges, free energy of binding, and interaction surface. Therefore, our current work provides a hypothesis for previous in vivo studies in the context of TLR signaling.
Highlights
Toll-like receptors (TLRs) are pattern-recognition receptors that trigger innate immune responses and prime antigen-specific adaptive immunity [1,2,3]
Once the TLR extracellular domain (ECD) is activated, Toll/interleukin (IL)-1 receptor (TIR) domains dimerize in the cytoplasm, thereby providing a specific scaffold that is required for the binding of downstream adaptor molecules to activate signaling pathways [6]
Viral dsRNA are recognized by the TLR3 subfamily, whereas nucleic acid PAMPs are recognized by the TLR7 subfamily (TLR7, 8 and 9) [9]
Summary
Toll-like receptors (TLRs) are pattern-recognition receptors that trigger innate immune responses and prime antigen-specific adaptive immunity [1,2,3]. Docking studies identified that the ligand-binding site was located near the undefined region, which along with diverse binding affinity might play a key role in TLR8 species-specificity. We used the recently published crystal structure of the TLR3/TLR3-dsRNA complex as a guide to predict the essential interacting dimerization residues in TLR8 and used those residues as a constraint during protein-protein docking study.
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