Abstract
We have disabled TNF receptor (TNFR) function by inducing allosteric modulation of tryptophan-107 (W107) in the receptor. The allosteric effect operates by means of an allosteric cavity found a short distance from a previously identified loop involved in ligand binding. Occupying this cavity by small molecules leads to perturbation of distal W107 and disables functions of the TNFR, a molecule not known to undergo conformational change upon binding TNF-alpha. TNF-alpha-induced NF-kappaB and p38 kinase activities and clinical symptoms of collagen-induced arthritis in mice were all diminished. Thus, disabling receptor function by induced conformational changes of active binding surfaces represents an innovative paradigm in structure-based drug design.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Allosteric Site / genetics
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Amino Acid Substitution
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Animals
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Arthritis, Experimental / genetics
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Arthritis, Experimental / immunology
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Arthritis, Experimental / pathology
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Arthritis, Experimental / prevention & control
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Base Sequence
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Cell Line
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DNA / genetics
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Humans
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In Vitro Techniques
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Male
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Mice
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Mice, Inbred DBA
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Models, Molecular
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Mutagenesis, Site-Directed
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NF-kappa B / metabolism
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Protein Conformation
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Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors
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Receptors, Tumor Necrosis Factor, Type I / chemistry*
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Receptors, Tumor Necrosis Factor, Type I / genetics
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Receptors, Tumor Necrosis Factor, Type I / metabolism*
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Signal Transduction
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Tryptophan / chemistry
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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NF-kappa B
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Receptors, Tumor Necrosis Factor, Type I
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Tumor Necrosis Factor-alpha
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Tryptophan
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DNA
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p38 Mitogen-Activated Protein Kinases