8JZM

The inhibitor of Toll-like receptor signaling o-vanillin binds covalently to MAL/TIRAP Lys-210

Summary for 8JZM

• Entry DOI: 10.2210/pdb8jzm/pdb
• Descriptor: Toll/interleukin-1 receptor domain-containing adapter protein (1 entity in total)
• Functional Keywords: toll-like receptor (tlr) signalling the cytoplasmic tir (toll/interleukin-1 receptor) domains, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 16031.20

Authors

Rahaman, M.H.,Jia, X.,Maxwell, M.J.,Mobli, M.,Kobe, B. (deposition date: 2023-07-05, release date: 2024-05-01)

Primary citation

Rahaman, M.H.,Thygesen, S.J.,Maxwell, M.J.,Kim, H.,Mudai, P.,Nanson, J.D.,Jia, X.,Vajjhala, P.R.,Hedger, A.,Vetter, I.,Haselhorst, T.,Robertson, A.A.B.,Dymock, B.,Ve, T.,Mobli, M.,Stacey, K.J.,Kobe, B.
o-Vanillin binds covalently to MAL/TIRAP Lys-210 but independently inhibits TLR2.
J Enzyme Inhib Med Chem, 39:2313055-2313055, 2024

PubMed Abstract: 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.

PubMed: 38416868
DOI: 10.1080/14756366.2024.2313055

Experimental method

SOLUTION NMR