Small-molecule inhibition of TNF-alpha
| Autor: | Molly M, He, Annemarie Stroustrup, Smith, Johan D, Oslob, William M, Flanagan, Andrew C, Braisted, Adrian, Whitty, Mark T, Cancilla, Jun, Wang, Alexey A, Lugovskoy, Josh C, Yoburn, Amy D, Fung, Graham, Farrington, John K, Eldredge, Eric S, Day, Leslie A, Cruz, Teresa G, Cachero, Stephan K, Miller, Jessica E, Friedman, Ingrid C, Choong, Brian C, Cunningham |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Indoles Chemical Phenomena Molecular Structure Chemistry Physical Protein Conformation Tumor Necrosis Factor-alpha Molecular Conformation Crystallography X-Ray Fluorescence Mass Spectrometry Kinetics Protein Subunits Models Chemical Receptors Tumor Necrosis Factor Type I Biotinylation Dimerization Hydrophobic and Hydrophilic Interactions Hydrogen |
| Zdroj: | Science (New York, N.Y.). 310(5750) |
| ISSN: | 1095-9203 |
| Popis: | We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-alpha activity in biochemical and cell-based assays with median inhibitory concentrations of 22 and 4.6 micromolar, respectively. Formation of an intermediate complex between the compound and the intact trimer results in a 600-fold accelerated subunit dissociation rate that leads to trimer dissociation. A structure solved by x-ray crystallography reveals that a single compound molecule displaces a subunit of the trimer to form a complex with a dimer of TNF-alpha subunits. |
| Databáze: | OpenAIRE |
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