Full metadata record
DC Field | Value | Language |
---|---|---|
dc.creator | Mancek-Keber, M. (Mateja) | - |
dc.creator | Gradisar, H. (Helena) | - |
dc.creator | Iñigo, M. (Melania) | - |
dc.creator | Martinez-de-Tejada, G. (Guillermo) | - |
dc.creator | Jerala, R. (Roman) | - |
dc.date.accessioned | 2013-07-19T07:39:15Z | - |
dc.date.available | 2013-07-19T07:39:15Z | - |
dc.date.issued | 2009 | - |
dc.identifier.citation | Mancek-Keber M, Gradisar H, Inigo Pestana M, Martinez de Tejada G, Jerala R. Free thiol group of MD-2 as the target for inhibition of the lipopolysaccharide-induced cell activation. J Biol Chem 2009 Jul 17;284(29):19493-19500. | es_ES |
dc.identifier.issn | 0021-9258 | - |
dc.identifier.uri | https://hdl.handle.net/10171/29511 | - |
dc.description.abstract | MD-2 is a part of the Toll-like 4 signaling complex with an indispensable role in activation of the lipopolysaccharide (LPS) signaling pathway and thus a suitable target for the therapeutic inhibition of TLR4 signaling. Elucidation of MD-2 structure provides a foundation for rational design of inhibitors that bind to MD-2 and inhibit LPS signaling. Since the hydrophobic binding pocket of MD-2 provides little specificity for inhibitors, we have investigated targeting the solvent-accessible cysteine residue within the hydrophobic binding pocket of MD-2. Compounds with affinity for the hydrophobic pocket that contain a thiol-reactive group, which mediates covalent bond formation with the free cysteine residue of MD-2, were tested. Fluorescent compounds 2-(4'-(iodoacetamido)anilino)naphthalene-6-sulfonic acid and N-pyrene maleimide formed a covalent bond with MD-2 through Cys(133) and inhibited LPS signaling. Cell activation was also inhibited by thiol-reactive compounds JTT-705 originally targeted against cholesterol ester transfer protein and antirheumatic compound auranofin. Oral intake of JTT-705 significantly inhibited endotoxin-triggered tumor necrosis factor alpha production in mice. The thiol group of MD-2 also represents the target of environmental or endogenous thiol-reactive compounds that are produced in inflammation. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | American Society for Biochemistry and Molecular Biology | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.subject | Lipopolysaccharides pharmacology | es_ES |
dc.subject | Lymphocyte Antigen 96 metabolism | es_ES |
dc.subject | Signal transduction drug effects | es_ES |
dc.subject | Toll-like receptors metabolism | es_ES |
dc.subject | Female | es_ES |
dc.title | Free thiol group of MD-2 as the target for inhibition of the lipopolysaccharide-induced cell activation | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.type.driver | info:eu-repo/semantics/article | es_ES |
dc.identifier.doi | http://dx.doi.org/10.1074/jbc.M109.003756 | es_ES |
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