Molecular recognition of a peptide mimic of the Lewis Y antigen by an anti-Lewis Y antibody.
Peptides as mimics of carbohydrates display a distinct advantage in vaccine design because of ease of synthesis and their inherent T cell-dependent nature as immunogens. While peptides that mimic carbohydrates have been described, it is not clear how they do so. To further our insight into structural relationships between peptide-mimics and carbohydrate structures, we have analyzed a potential recognition scheme between the murine monoclonal antibody, B3, directed against the tumor-associated antigen Lewis Y oligosaccharide and a peptide identified from phage display screening with B3. The Lewis Y core antigen is a difucosylated structure consisting of four hexose units. The B3 antibody binds to the peptide sequence APWLYGPA in which the putative sequence APWLY is critical for binding to the antibody. Not having experimental structural information for B3, the crystal structure of another anti-Lewis Y antibody, BR96, solved in complex with a nonoate methyl ester Lewis Y tetrasaccharide, provides a molecular basis for LeY antigen recognition and specificity, and how this binding relates to peptide binding. As a guide to place the APWLY motif in the B3 combining site, a fragment library was searched for analogous compounds that have the potential to bind to B3. Our modeling study shows that the B3-peptide complex shares similar recognition features for the difucosylated type 2 lactoseries' structure. This analysis provides a molecular perspective for peptide mimicry of a carbohydrate epitope.
Murali
R
R
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Kieber-Emmons
T
T
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D000918:Antibody Specificity; D001666:Binding Sites, Antibody; D002236:Carbohydrate Conformation; D002241:Carbohydrates / Q000276:immunology*; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007983:Lewis Blood Group Antigens / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D011487:Protein Conformation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D000911:Antibodies, Monoclonal; D002241:Carbohydrates; D000939:Epitopes; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D010455:Peptides