title: Structural insights into antibody recognition of mycobacterial polysaccharides.
abstract: Mycobacteria are major human pathogens responsible for such serious and widespread diseases as tuberculosis and leprosy. Among the evolutionary adaptations essential for pathogenicity in mycobacteria is a complex carbohydrate-rich cell-wall structure that contains as a major immunomodulatory molecule the polysaccharide lipoarabinomannan (LAM). We report here crystal structures of three fragments from the non-reducing termini of LAM in complex with a murine antibody Fab fragment (CS-35Fab). These structures reveal for the first time the three-dimensional structures of key components of LAM and the molecular basis of LAM recognition at between 1.8- and 2.0-A resolution. The antigen-binding site of CS-35Fab forms three binding pockets that show a high degree of complementarity to the reducing end, the branch point and one of the non-reducing ends of the Y-shaped hexasaccharide moiety found at most of the non-reducing termini of LAM. Structures of CS-35Fab bound to two additional tetrasaccharides confirm the general mode of binding seen in the hexasaccharide and indicate how different parts of LAM are recognized. Altogether, these structures provide a rational basis for understanding the overall architecture of LAM and identify the key elements of an epitope that may be exploited for the development of novel and more effective anti-mycobacterial vaccines. Moreover, this study represents the first high-resolution X-ray crystallographic investigation of oligofuranoside-protein recognition.
authors: Alberta Ingenuity Centre for Carbohydrate Science, University of Calgary, Calgary, Alberta, Canada.
authors: Tomohiko
authors: T
authors: Murase
authors: Ruixiang Blake
authors: RB
authors: Zheng
authors: Maju
authors: M
authors: Joe
authors: Yu
authors: Y
authors: Bai
authors: Sandra L
authors: SL
authors: Marcus
authors: Todd L
authors: TL
authors: Lowary
authors: Kenneth K S
authors: KK
authors: Ng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000907:Antibodies, Bacterial / Q000737:chemistry* / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D002240:Carbohydrate Sequence; D018360:Crystallography, X-Ray; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009161:Mycobacterium / Q000737:chemistry* / Q000276:immunology; D011135:Polysaccharides, Bacterial / Q000737:chemistry* / Q000276:immunology; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D011135:Polysaccharides, Bacterial; C050016:lipoarabinomannan