title: Energetics of Endotoxin Recognition in the Toll-Like Receptor 4 Innate Immune Response.
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.
authors.affiliation: Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Paramo
authors.affiliation: Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.|Current Address: Cresset Biomolecular Discovery, New Cambridge House, Bassingbourn Road, Litlington SG8 0SS, UK.
authors.forename: Susana M
authors.initials: SM
authors.lastname: Tomasio
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Irvine
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Bryant
authors.affiliation: Bioinformatics Institute (A*STAR), 30 Biopolis Str, #07-01 Matrix, Singapore 138671.|Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543 Singapore.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
mesh_terms: D004731:Endotoxins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4