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Taxanes inhibit human TLR4 signaling by binding to MD-2
Authors:Resman Nusa  Gradisar Helena  Vasl Jozica  Keber Mateja Mancek  Pristovsek Primoz  Jerala Roman
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
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.
Keywords:Paclitaxel  Docetaxel  MD-2  Lipopolysaccharide  Toll-like receptor 4
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