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: 9.67). 09/2005; 102(31):10970-5. DOI: 10.1073/pnas.0504301102
Source: PubMed


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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    • "However, it seems intractable to disrupt TNF-a/TNFR1 interaction with small compounds, because the TNF-a–TNFR1 binding event capitalizes on avidity effects [25] and utilizes a large surface area for interaction [26] [27]. Historically, the discovery of small molecules that potently disrupt the TNF-a/ TNFR1 interaction has proven difficult, and attempts to design a small-molecule TNF-a antagonist based on the three-dimensional structural information of TNF-a and TNFR1 were also not successful in identifying an antagonist that would selectively inhibit the TNF/TNFR1 interaction and would have sufficient therapeutic effect [28] [29] [30]. Medicinal plant-derived compounds have been a major source of pharmacologically active substances from which drugs can be developed. "
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    ABSTRACT: Anti-TNF biologics are effective therapies for various inflammatory diseases. Unfortunately, their clinical use is associated with an increased risk of infections. Selectively inhibiting TNF receptor-1 (TNFR1)-mediated signaling while preserving TNFR2 signaling may reduce inflammation yet maintain host immune response to pathogens. However, few small molecules that selectively target the TNF/TNFR system have been discovered. In the present study, we identified Japonicone A (Jap A), a nature compound derived from Inula japonica Thunb, as a novel TNF-α antagonist, as it reduced the TNF-α-mediated cytotoxicity on L929 cells and inhibited the binding of (125)I-labeled TNF-α to L929 cell surface. Furthermore, Jap A could directly bind to TNF-α rather than TNFR1 as determined by surface plasmon resonance. More importantly, Jap A could effectively inhibit the binding of TNF-α to TNFR1, while displaying only marginal inhibitory effects on that to TNFR2. Jap A also could block TNFR1-mediated signaling as it inhibited TNF-α-induced NF-κB activation in 293 cells. In addition, Jap A suppressed TNF-α-induced expressions of adhesion molecules (ICAM-1, VCAM-1) and chemokine (MCP-1) in the endothelial cells by blocking TNF-α-triggered multiple signaling pathways. Data from in vivo experiments demonstrated that Jap A protected mice from acute hepatitis induced by TNF-α/d-galactosamine, but did not compromise host antiviral immunity in adenovirus-infected mice. These results indicate that Jap A can directly target TNF-α, selectively disrupt its interaction with TNFR1, and antagonize its pro-inflammatory activities without compromising host defense against virus, thus emphasizing the potential of Jap A as an interesting lead compound for development of new anti-inflammatory drugs.
    Biochemical pharmacology 09/2012; 84(11). DOI:10.1016/j.bcp.2012.08.025 · 5.01 Impact Factor
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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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    ABSTRACT: Increasing evidence favors the notion that, before triggering, the T cell antigen receptor (TCR) forms nanometer-scale oligomers that are called nanoclusters. The organization of the TCR in pre-existing oligomers cannot be ignored when analyzing the properties of ligand (pMHC) recognition and signal transduction. As with other membrane receptors, the existence of TCR oligomers points out to cooperativity phenomena. We review the data in support of conformational changes in the TCR as the basic principle to transduce the activation signal to the cytoplasm and the incipient data suggesting cooperativity within nanoclusters.
    Frontiers in Immunology 05/2012; 3:115. DOI:10.3389/fimmu.2012.00115
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    • "CIA was induced in DBA/1 male mice at age six to eight weeks by intradermal injection of 100 µg of chicken type II collagen (Sigma) in complete Freund's adjuvant on day 0 followed by intraperitoneal (i.p.) injection of 100 µg collagen in PBS on day 21 (Murali et al. 2005). VPA (400 mg/kg) or PBS was administered i.p. daily, starting on day 21 of the study. "
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    ABSTRACT: Collagen-induced arthritis (CIA) is an established mouse model of disease with hallmarks of clinical rheumatoid arthritis. Histone/protein deacetylase inhibitors (HDACi) are known to inhibit the pathogenesis of CIA and other models of autoimmune disease, although the mechanisms responsible are unclear. Regulatory T cell (Treg) function is defective in rheumatoid arthritis. FOXP3 proteins in Tregs are present in a dynamic protein complex containing histone acetyltransferase and HDAC enzymes, and FOXP3 itself is acetylated on lysine residues. We therefore investigated the effects of HDACi therapy on regulatory T cell function in the CIA model. Administration of an HDACi, valproic acid (VPA), significantly decreased disease incidence (p<0.005) and severity (p<0.03) in CIA. In addition, VPA treatment increased both the suppressive function of CD4(+)CD25(+) Tregs (p<0.04) and the numbers of CD25(+)FOXP3(+) Tregs in vivo. Hence, clinically approved HDACi such as VPA may limit autoimmune disease in vivo through effects on the production and function of FOXP3(+) Treg cells.
    Experimental and Molecular Pathology 08/2009; 87(2):99-104. DOI:10.1016/j.yexmp.2009.06.003 · 2.71 Impact Factor
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