Structural basis for selective cross-reactivity in a bactericidal antibody against inner core lipooligosaccharide from Neisseria meningitidis.
The structure of a antigen-binding fragment (Fab) from the bactericidal monoclonal antibody LPT3-1 specific to lipooligosaccharide (LOS) inner cores from Neisseria meningitidis has been solved in complex with an eight-sugar inner core fragment NmL3 galE lpt3 KOH to 2.69 Å resolution. The epitope is centered about an inner core N-acetylglucosamine residue unique to N. meningitidis and does not include the lipid A moiety, which is disordered in the structure, but is positioned to allow the binding of free and membrane-anchored full-length LOS. All the amino acid residues that contact antigen are of germline origin but, remarkably, two consecutive somatic mutations of serine to glycine in the heavy chain at residues 52 and 52a are positioned to deprive the antibody of advantageous interactions and so weaken binding. However, these mutations are key to allowing selective cross-reactivity with the HepII-3-PEtn inner core variant expressed by 70% of strains. Neisseria meningitidis is a leading cause of disease in the developed world and is especially dangerous to children, who lack the necessary protective antibodies. The structure of Fab LPT3-1 in complex with LOS provides insight into the antibody's selective ability to recognize multiple clinically relevant variations of the LOS inner core from N. meningitidis.
Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada V8P 3P6.
Matthew J
MJ
Parker
Kathryn
K
Gomery
Gabrielle
G
Richard
C Roger
CR
MacKenzie
Andrew D
AD
Cox
James C
JC
Richards
Stephen V
SV
Evans
D000818:Animals; D000907:Antibodies, Bacterial / Q000737:chemistry*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000737:chemistry*; D002236:Carbohydrate Conformation; D003429:Cross Reactions; D051379:Mice; D009345:Neisseria meningitidis / Q000737:chemistry*; D009844:Oligosaccharides / Q000737:chemistry*
D000907:Antibodies, Bacterial; D058846:Antibodies, Monoclonal, Murine-Derived; D009844:Oligosaccharides
Neisseria meningitidis; X-ray crystallography; antibody; cross-reactivity; lipooligosaccharides