Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Biotinylation
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Chemical Phenomena
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Chemistry, Physical
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Crystallography, X-Ray
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Dimerization
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Fluorescence
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Hydrogen / chemistry
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Hydrophobic and Hydrophilic Interactions
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Indoles / chemical synthesis
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Indoles / chemistry*
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Indoles / pharmacology*
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Kinetics
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Mass Spectrometry
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Models, Chemical
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Models, Molecular
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Molecular Conformation
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Molecular Structure
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Protein Conformation
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Protein Subunits / chemistry
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / chemistry*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Indoles
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Protein Subunits
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Receptors, Tumor Necrosis Factor, Type I
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SPD00000304
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Tumor Necrosis Factor-alpha
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Hydrogen