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Title: Structural basis for antibody targeting of the broadly expressed microbial polysaccharide poly-N-acetylglucosamine.
Austin Authors: Soliman, Caroline;Walduck, Anna K;Yuriev, Elizabeth;Richards, Jack S;Cywes-Bentley, Colette;Pier, Gerald B;Ramsland, Paul A 
Affiliation: School of Science, Royal Melbourne Institute of Technology (RMIT) University, Bundoora, Victoria, Australia
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia
Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, Victoria, Australia
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
Department of Infectious Diseases, Central Clinical School, Alfred Hospital, Melbourne, Victoria, Australia
Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts
Department of Immunology, Central Clinical School, Monash University, Victoria, Melbourne, Australia
Department of Surgery, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Issue Date: 6-Apr-2018 2018-02-15
Publication information: The Journal of biological chemistry 2018; 293(14): 5079-5089
Abstract: In response to the widespread emergence of antibiotic-resistant microbes, new therapeutic agents are required for many human pathogens. A non-mammalian polysaccharide, poly-N-acetyl-d-glucosamine (PNAG), is produced by bacteria, fungi, and protozoan parasites. Antibodies that bind to PNAG and its deacetylated form (dPNAG) exhibit promising in vitro and in vivo activities against many microbes. A human IgG1 mAb (F598) that binds both PNAG and dPNAG has opsonic and protective activities against multiple microbial pathogens and is undergoing preclinical and clinical assessments as a broad-spectrum antimicrobial therapy. Here, to understand how F598 targets PNAG, we determined crystal structures of the unliganded F598 antigen-binding fragment (Fab) and its complexes with N-acetyl-d-glucosamine (GlcNAc) and a PNAG oligosaccharide. We found that F598 recognizes PNAG through a large groove-shaped binding site that traverses the entire light- and heavy-chain interface and accommodates at least five GlcNAc residues. The Fab-GlcNAc complex revealed a deep binding pocket in which the monosaccharide and a core GlcNAc of the oligosaccharide were almost identically positioned, suggesting an anchored binding mechanism of PNAG by F598. The Fab used in our structural analyses retained binding to PNAG on the surface of an antibiotic-resistant, biofilm-forming strain of Staphylococcus aureus Additionally, a model of intact F598 binding to two pentasaccharide epitopes indicates that the Fab arms can span at least 40 GlcNAc residues on an extended PNAG chain. Our findings unravel the structural basis for F598 binding to PNAG on microbial surfaces and biofilms.
DOI: 10.1074/jbc.RA117.001170
PubMed URL: 29449370
Type: Journal Article
Subjects: Staphylococcus aureus (S. aureus)
antibiotic resistance
antibody structure
carbohydrate-binding protein
crystal structure
monoclonal antibody
vaccine development
Appears in Collections:Journal articles

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