Article: Free thiol group of MD-2 as the target for inhibition of the lipopolysaccharide-induced cell activation.
The Journal of biological chemistry
2009 Volume 284, Issue 29, Page(s) 19493–19500
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 ... ...
| 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. |
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| MeSH term(s) | Animals ; Auranofin/chemistry ; Auranofin/metabolism ; Auranofin/pharmacology ; Binding Sites ; Cell Line ; Cysteine/chemistry ; Cysteine/metabolism ; Dose-Response Relationship, Drug ; Female ; Humans ; Lipopolysaccharides/metabolism ; Lipopolysaccharides/pharmacology ; Lymphocyte Antigen 96/chemistry ; Lymphocyte Antigen 96/metabolism ; Maleimides/chemistry ; Maleimides/metabolism ; Maleimides/pharmacology ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Molecular Structure ; Protein Binding ; Protein Structure, Tertiary ; Pyrenes ; Signal Transduction/drug effects ; Sulfhydryl Compounds/chemistry ; Sulfhydryl Compounds/metabolism ; Sulfhydryl Compounds/pharmacology ; Toll-Like Receptors/metabolism ; Tumor Necrosis Factor-alpha/blood |
| Chemical Substances | Lipopolysaccharides ; Lymphocyte Antigen 96 ; Maleimides ; Pyrenes ; Sulfhydryl Compounds ; Toll-Like Receptors ; Tumor Necrosis Factor-alpha ; dalcetrapib (3D050LIQ3H) ; Auranofin (3H04W2810V) ; pyrene (9E0T7WFW93) ; N-(3-pyrene)maleimide (9SZY1M545Z) ; Cysteine (K848JZ4886) |
| Language | English |
| Publishing date | 2009-05-27 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2997-x |
| ISSN | 1083-351X ; 0021-9258 |
| ISSN (online) | 1083-351X |
| ISSN | 0021-9258 |
| DOI | 10.1074/jbc.M109.003756 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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