Structural study of Toll-like receptor 5 and its ligand complexes

Abstract

Toll-like receptor 5(TLR5) recognizes bacterial flagellin and is expressed in immune cells as well as epithelial cells in lung and intestine. As a result of TLR5 activation, several therapeutic effects have been reported recently. Also it has been reported that gut commensal bacterial flagellins like Roseburia bind to TLR5 strongly but evoke weak TLR5 signaling. Based on this, I report two research aims for TLR5 and its ligand complexes. First, I researched structure-based drug discovery for geriatric diseases by analyzing TLR5-drug complex structure. I succeeded expression of TLR5 ectodomain(LRRNT~LRR15) hybridized with variable lymphocyte receptor(VLR) by analyzing each LRR motifs. And then I confirmed binding behavior between hTLR5(or drTLR5) and drug candidate based on gel filtration chromatography(GFC) and micro-scale thermophoresis(MST). Second, I researched novel mechanism how microbiome flagellins bind TLR5 with high affinity but activate it slightly. I purified gut commensal flagellin, RhFlaB and binding effect is confirmed by GFC-based HPLC pick shift. If TLR5 and its ligand complex structures are solved like above, it will be helpful to understand TLR5 activation mechanism of flagellin D0 domain and It will also be useful to develop TLR5 agonistic treatment.