Taxanes inhibit human TLR4 signaling by binding to MD-2 |
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Authors: | Resman Nusa Gradisar Helena Vasl Jozica Keber Mateja Mancek Pristovsek Primoz Jerala Roman |
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Institution: | a Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia b Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia |
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Abstract: | 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. |
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Keywords: | Paclitaxel Docetaxel MD-2 Lipopolysaccharide Toll-like receptor 4 |
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