Taxanes inhibit human TLR4 signaling by binding to MD-2

• Published in: FEBS letters 2008-11, Vol.582 (28), p.3929-3934
• Main Authors: Resman, Nuša, Gradišar, Helena, Vašl, Jožica, Keber, Mateja Manček, Pristovšek, Primož, Jerala, Roman
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line; Docetaxel; Humans; Lipopolysaccharide; Lipopolysaccharides - immunology; Lipopolysaccharides - pharmacology; Lymphocyte Antigen 96 - metabolism; MD-2; Paclitaxel; Paclitaxel - chemistry; Paclitaxel - metabolism; Paclitaxel - pharmacology; Signal Transduction - drug effects; Taxoids - chemistry; Taxoids - metabolism; Taxoids - pharmacology; Toll-like receptor 4; Toll-Like Receptor 4 - agonists; Toll-Like Receptor 4 - antagonists & inhibitors; Toll-Like Receptor 4 - metabolism
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2008.10.037

LPS is the primary ligand of Toll-like receptor 4, activating it through binding to its accessory protein MD-2. Murine but not human cells expressing MD-2/TLR4 are also activated by paclitaxel. Paclitaxel binds to human MD-2. The binding site of paclitaxel overlaps with the binding site of bis-ANS and LPS, which results in the ability of taxanes to inhibit LPS signaling in the system with human receptors. Circular dichroic spectra of human MD-2 indicated differences in the chemical environment in the presence of paclitaxel and docetaxel. Molecular docking identified the interacting residues of MD-2 and suggests that hydrophobic interactions govern the binding, while the C-3′N group where the paclitaxel and docetaxel differ is exposed on the surface of MD-2.