Disabling TNF receptor signaling by induced conformational perturbation of tryptophan-107.

Department of Pathology and Laboratory of Medicine and Abramson Cancer Research Center, University of Pennsylvania, 36th Hamilton Walk, Philadelphia, PA 19104, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2005; 102(31):10970-5. DOI: 10.1073/pnas.0504301102
Source: PubMed

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.

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Available from: Ramachandran Murali, Mar 12, 2014
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