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Rahaman, Md Habibur; Thygesen, Sara J; Maxwell, Michael J; Kim, Hyoyoung; Mudai, Prerna; Nanson, Jeffrey D; Jia, Xinying; Vajjhala, Parimala R; Hedger, Andrew; Vetter, Irina; Haselhorst, Thomas; Robertson, Avril A B; Dymock, Brian; Ve, Thomas; Mobli, Mehdi; Stacey, Katryn J; Kobe, Bostjan
Journal of enzyme inhibition and medicinal chemistry 39, Issue: 1Journal Article
Toll-like receptor (TLR) innate immunity signalling protects against pathogens, but excessive or prolonged signalling contributes to a range of inflammatory conditions. Structural information on the TLR cytoplasmic TIR (Toll/interleukin-1 receptor) domains and the downstream adaptor proteins can help us develop inhibitors targeting this pathway. The small molecule o-vanillin has previously been reported as an inhibitor of TLR2 signalling. To study its mechanism of action, we tested its binding to the TIR domain of the TLR adaptor MAL/TIRAP (MAL ). We show that o-vanillin binds to MAL and inhibits its higher-order assembly . Using NMR approaches, we show that o-vanillin forms a covalent bond with lysine 210 of MAL. We confirm in mouse and human cells that o-vanillin inhibits TLR2 but not TLR4 signalling, independently of MAL, suggesting it may covalently modify TLR2 signalling complexes directly. Reactive aldehyde-containing small molecules such as o-vanillin may target multiple proteins in the cell.
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