Article

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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    • "More recently, it has been shown that transmission of the active conformation requires extensive rearrangement of the transmembrane domains of the GPCRs (Altan-Bonnet and Germain, 2005; Adler et al., 2008). Many receptors with intrinsic tyrosine kinase activity also undergo ligand-induced conformational changes (Jiang and Hunter, 1999), as well as several receptors of immunological interest, including: integrins, the erythropoietin receptor, the tumor necrosis factor receptors, Fas, the interleukin 6 receptor, IFN receptors (Banner et al., 1993; Walter et al., 1995; Remy et al., 1999; Chan et al., 2000; Siegel et al., 2000; Krause et al., 2002; Murali et al., 2005; Strunk et al., 2008), and most important, Abbreviations: EM, electron microscopy; FRET, Forester's resonance energy transfer ; GPCRs, G-protein-coupled receptors; ITAM, immunoreceptor tyrosine-based activation motif; NMR, nuclear magnetic resonance; pMHC, major histocompatibility complex loaded with antigen peptide; PRS, proline-rich sequence; TCR, T cell antigen receptor. the B cell receptor (Cambier et al., 1994; Reth, 2002; Tolar et al., 2005; Yang and Reth, 2010). "
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