title: Taxanes inhibit human TLR4 signaling by binding to MD-2.
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.
authors.affiliation: Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.
authors.forename: Nusa
authors.initials: N
authors.lastname: Resman
authors.forename: Helena
authors.initials: H
authors.lastname: Gradisar
authors.forename: Jozica
authors.initials: J
authors.lastname: Vasl
authors.forename: Mateja Mancek
authors.initials: MM
authors.lastname: Keber
authors.forename: Primoz
authors.initials: P
authors.lastname: Pristovsek
authors.forename: Roman
authors.initials: R
authors.lastname: Jerala
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D000077143:Docetaxel; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000378:metabolism*; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; C495345:TLR4 protein, human; D043823:Taxoids; D051197:Toll-Like Receptor 4; D000077143:Docetaxel; D017239:Paclitaxel