Structural insights into antibody recognition of mycobacterial polysaccharides.
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.
Murase
Tomohiko
T
Alberta Ingenuity Centre for Carbohydrate Science, University of Calgary, Calgary, Alberta, Canada.
Zheng
Ruixiang Blake
RB
Joe
Maju
M
Bai
Yu
Y
Marcus
Sandra L
SL
Lowary
Todd L
TL
Ng
Kenneth K S
KK
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
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D011135:Polysaccharides, Bacterial; C050016:lipoarabinomannan