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Title: Energetics of Endotoxin Recognition in the Toll-Like Receptor 4 Innate Immune Response
Authors: Paramo, T
Tomasio, S.M
Irvine, K.L
Bryant, C.E
Bond, P.J 
Keywords: endotoxin
protein binding
protein MD 2
toll like receptor 4
innate immunity
molecular model
signal transduction
structure activity relation
Immunity, Innate
Lymphocyte Antigen 96
Models, Molecular
Molecular Conformation
Protein Binding
Signal Transduction
Structure-Activity Relationship
Toll-Like Receptor 4
Issue Date: 2015
Publisher: Nature Publishing Group
Citation: Paramo, T, Tomasio, S.M, Irvine, K.L, Bryant, C.E, Bond, P.J (2015). Energetics of Endotoxin Recognition in the Toll-Like Receptor 4 Innate Immune Response. Scientific Reports 5 : 17997. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Bacterial outer membrane lipopolysaccharide (LPS) potently stimulates the mammalian innate immune system, and can lead to sepsis, the primary cause of death from infections. LPS is sensed by Toll-like receptor 4 (TLR4) in complex with its lipid-binding coreceptor MD-2, but subtle structural variations in LPS can profoundly modulate the response. To better understand the mechanism of LPS-induced stimulation and bacterial evasion, we have calculated the binding affinity to MD-2 of agonistic and antagonistic LPS variants including lipid A, lipid IVa, and synthetic antagonist Eritoran, and provide evidence that the coreceptor is a molecular switch that undergoes ligand-induced conformational changes to appropriately activate or inhibit the receptor complex. The plasticity of the coreceptor binding cavity is shown to be essential for distinguishing between ligands, whilst similar calculations for a model bacterial LPS bilayer reveal the €membrane-like€ nature of the protein cavity. The ability to predict the activity of LPS variants should facilitate the rational design of TLR4 therapeutics.
Source Title: Scientific Reports
ISSN: 2045-2322
DOI: 10.1038/srep17997
Rights: Attribution 4.0 International
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