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Recent Research from University of Cambridge Highlight Findings in Pattern Recognition Receptors

January 31, 2014



By a News Reporter-Staff News Editor at Health & Medicine Week -- Investigators publish new report on Immunology. According to news reporting originating from Cambridge, United Kingdom, by NewsRx correspondents, research stated, "Toll-like receptor 4 (TLR4) in complex with MD-2 stimulates innate immunological pathways in response to bacterial lipopolysaccharide (LPS). Molecular simulations reveal the mechanism of TLR4 complex signaling in response to agonists or antagonists."

Our news editors obtained a quote from the research from the University of Cambridge, "Conserved clamshell motions in MD-2 allosterically signal ligand-bound state via the conserved phenylalanine 126 residue to TLR4. The structural basis for molecular switching during endotoxin-induced TLR4 activation is revealed in atomic detail. As part of the innate immune system, Toll-like receptor 4 (TLR4) recognizes bacterial cell surface lipopolysaccharide (LPS) by forming a complex with a lipid-binding co-receptor, MD-2. In the presence of agonist, TLR4MD-2 dimerizes to form an active receptor complex, leading to initiation of intracellular inflammatory signals. TLR4 is of great biomedical interest, but its pharmacological manipulation is complicated because even subtle variations in the structure of LPS can profoundly impact the resultant immunological response. Here, we use atomically detailed molecular simulations to gain insights into the nature of the molecular signaling mechanism. We first demonstrate that MD-2 is extraordinarily flexible. The clamshell-like motions of its -cup fold enable it to sensitively match the volume of its hydrophobic cavity to the size and shape of the bound lipid moiety. We show that MD-2 allosterically transmits this conformational plasticity, in a ligand-dependent manner, to a phenylalanine residue (Phe-126) at the cavity mouth previously implicated in TLR4 activation."

According to the news editors, the research concluded: "Remarkably, within the receptor complex, we observe spontaneous transitions between active and inactive signaling states of Phe-126, and we confirm that Phe-126 is indeed the molecular switch in endotoxic signaling."

For more information on this research see: The Structural Basis for Endotoxin-induced Allosteric Regulation of the Toll-like Receptor 4 (TLR4) Innate Immune Receptor. Journal of Biological Chemistry, 2013;288(51):36215-36225. Journal of Biological Chemistry can be contacted at: Amer Soc Biochemistry Molecular Biology Inc, 9650 Rockville Pike, Bethesda, MD 20814-3996, USA. (American Society for Biochemistry and Molecular Biology - www.asbmb.org; Journal of Biological Chemistry - www.jbc.org/)

The news editors report that additional information may be obtained by contacting T. Paramo, University of Cambridge, Dept. of Vet Med, Cambridge CB3 0ES, United Kingdom. Additional authors for this research include T.J. Piggot, C.E. Bryant and P.J. Bond (see also Immunology).

Keywords for this news article include: Europe, Cambridge, Endotoxins, Immunology, United Kingdom, Nanotechnology, Bacterial Toxins, Membrane Proteins, Molecular Switches, Toll-Like Receptor 4, Emerging Technologies, Pattern Recognition Receptors

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Source: Health & Medicine Week


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