title: Antibody WN1 222-5 mimics Toll-like receptor 4 binding in the recognition of LPS.
abstract: Escherichia coli infections, a leading cause of septic shock, remain a major threat to human health because of the fatal action to endotoxin (LPS). Therapeutic attempts to neutralize endotoxin currently focus on inhibiting the interaction of the toxic component lipid A with myeloid differentiating factor 2, which forms a trimeric complex together with Toll-like receptor 4 to induce immune cell activation. The 1.73-Å resolution structure of the unique endotoxin-neutralizing protective antibody WN1 222-5 in complex with the core region shows that it recognizes LPS of all E. coli serovars in a manner similar to Toll-like receptor 4, revealing that protection can be achieved by targeting the inner core of LPS and that recognition of lipid A is not required. Such interference with Toll-like receptor complex formation opens new paths for antibody sepsis therapy independent of lipid A antagonists.
authors.affiliation: Department of Biochemistry and Microbiology,  University of Victoria, Victoria, BC,  Canada V8P 3P6.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Gomery
authors.forename: Sven
authors.initials: S
authors.lastname: Müller-Loennies
authors.forename: Cory L
authors.initials: CL
authors.lastname: Brooks
authors.forename: Lore
authors.initials: L
authors.lastname: Brade
authors.forename: Paul
authors.initials: P
authors.lastname: Kosma
authors.forename: Franco
authors.initials: F
authors.lastname: Di Padova
authors.forename: Helmut
authors.initials: H
authors.lastname: Brade
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Evans
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D000936:Antigen-Antibody Complex; D002241:Carbohydrates / Q000737:chemistry; D004731:Endotoxins / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008070:Lipopolysaccharides / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D012772:Shock, Septic / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000737:chemistry*
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D002241:Carbohydrates; D004731:Endotoxins; D008024:Ligands; D008055:Lipids; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4