O-Vanillin Binds Covalently to MAL/TIRAP Lys-210 but Independently Inhibits TLR2

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2024 Feb 28

PMID 38416868

Authors

Md Habibur Rahaman

Sara J Thygesen

Michael J Maxwell

Hyoyoung Kim

Prerna Mudai

Jeffrey D Nanson

Xinying Jia

Parimala R Vajjhala

Andrew Hedger

Irina Vetter

Thomas Haselhorst

Avril A B Robertson

Brian Dymock

Thomas Ve

Mehdi Mobli

Katryn J Stacey

Bostjan Kobe

Affiliations

Soon will be listed here.

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.

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