Structure and dynamic behavior of Toll‐like receptor 2 subfamily triggered by malarial glycosylphosphatidylinositols of Plasmodium falciparum

Abstract

Proinflammatory responses by Toll‐like receptors (TLRs) to malaria infection are considered to be a significant factor in suppressing pathogen growth and in disease control. The key protozoan parasite Plasmodium falciparum causes malaria through glycosylphosphatidylinositols (GPIs), which induce the host immune response mainly via TLR2 signalling. Experimental studies have suggested that malarial GPIs from P. falciparum are recognized by the TLR2 subfamily. However, the interaction site and their involvement in the activation mechanism are still unknown. A better understanding of the detailed structure of the TLR–GPI interaction is important for the design of more effective anti‐malarial therapeutics. We used a molecular docking method to predict the binding regions of malarial GPIs with the TLR2 subfamily members. We also employed molecular dynamics simulations and principal component analysis to understand ligand‐induced conformational changes of the TLR2 subfamily. We observed the expected structural changes upon ligand binding, and significant movements were found in loop regions located in the ligand‐binding site of the TLR2 subfamily. We further propose that the binding modes of malarial GPIs are similar to lipopeptides, and that the lipid portions of the ligands could play an essential role in selective dimerization of the TLR2 subfamily.

Toll‐like receptor 1 and 10 variations increase asthma risk and review highlights further research directions

“…TLRs 1, 6 and 10 are able to function as co‐receptors for TLR2, and therefore, the group has been called the TLR2 subfamily. The TLR 1 , 2 , 6 and 10 genes are located in close proximity to each other in chromosome 4 and the proteins encoded by these genes form molecules that act as TLR1/2, TLR6/2 and TLR10/2 receptor dimers . TLR1/2 and TLR6/2 were originally reported to recognise bacterial cell components, but there is currently accumulating evidence that these receptor dimers can also be activated by viruses, including the RSV and rhinoviruses .…”

STING-Licensed Macrophages Prime Type I IFN Production by Plasmacytoid Dendritic Cells in the Bone Marrow during Severe Plasmodium yoelii Malaria

“…Major Plasmodium parasite molecules sensed by the host immune system include glycophosphatidylinositol (GPI), haemozoin crystals and nucleic acids. GPI anchors trigger TLR2/TLR1 and TLR2/TLR6 heterodimers -and to some extent TLR4-, leading to the production of pro-inflammatory cytokines (TNF, IL-1β) via MyD88 [26, 27], reactive nitrogen and oxygen species [28, 29], and the upregulation of adhesion molecules (ICAM1, VCAM1)[30]. Haemozoin crystals result from haemoglobin digestion by blood stage Plasmodium parasites which stimulate massive secretion of IL-1β, TNF and chemokines.…”

Toll‐like receptor 2 antagonists identified through virtual screening and experimental validation

“…Likewise, the microbial components that modulate TLR2 signaling are unsafe as drugs, due to their toxic nature [40]. Nevertheless, in our previous studies, we used the molecular docking approach for TLR2 subfamily members, to successfully predict their high molecular mass TLR2 agonists and their binding modes [20,41]. The development of analogs for existing high molecular mass structures may yield compounds with poor pharmacokinetic properties.…”

“…However, the identification of TLR2 small-molecule modulators through computational methods is one of the most challenging tasks in drug discovery, due to the expansive TLR2-TLR1/TLR6 interfaces. Nevertheless, in our previous studies, we used the molecular docking approach for TLR2 subfamily members, to successfully predict their high molecular mass TLR2 agonists and their binding modes [20,41]. In this study, we adopted a VS method that integrates protein-ligand-based and ligand-based pharmacophore approaches to identify TLR2 antagonists.…”