Structural Insights into VLR Fine Specificity for Blood Group Carbohydrates

Structure. 2017 Nov 7;25(11):1667-1678.e4. doi: 10.1016/j.str.2017.09.003. Epub 2017 Oct 5.


High-quality reagents to study and detect glycans with high specificity for research and clinical applications are severely lacking. Here, we structurally and functionally characterize several variable lymphocyte receptor (VLR)-based antibodies from lampreys immunized with O erythrocytes that specifically recognize the blood group H-trisaccharide type II antigen. Glycan microarray analysis and biophysical data reveal that these VLRs exhibit greater specificity for H-trisaccharide compared with the plant lectin UEA-1, which is widely used in blood typing. Among these antibodies, O13 exhibits superior specificity for H-trisaccharide, the basis for which is revealed by comparative analysis of high-resolution VLR:glycan crystal structures. Using a structure-guided approach, we designed an O13 mutant with further enhanced specificity for H-trisaccharide. These insights into glycan recognition by VLRs suggest that lampreys can produce highly specific glycan antibodies, and are a valuable resource for the production of next-generation glycan reagents for biological and biomedical research and as diagnostics and therapeutics.

Keywords: X-ray crystallography; glycans; glycobiology; glycomics; immunology; leucine-rich repeat; structural biology; variable lymphocyte receptor.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / biosynthesis
  • Antibodies, Monoclonal / chemistry*
  • Antibodies, Monoclonal / isolation & purification
  • Antibody Specificity
  • Binding Sites
  • Blood Group Antigens / analysis*
  • Blood Group Antigens / immunology
  • Blood Grouping and Crossmatching / methods
  • Crystallography, X-Ray
  • Erythrocytes / chemistry
  • Erythrocytes / immunology
  • Humans
  • Immunization
  • Lampreys / immunology*
  • Models, Molecular
  • Plant Lectins / chemistry
  • Plant Lectins / immunology
  • Polysaccharides / chemistry*
  • Polysaccharides / immunology
  • Polysaccharides / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Receptors, Antigen, T-Cell / chemistry*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Trisaccharides / chemistry*
  • Trisaccharides / immunology
  • Trisaccharides / metabolism


  • Antibodies, Monoclonal
  • Blood Group Antigens
  • Plant Lectins
  • Polysaccharides
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins
  • Trisaccharides
  • Ulex europaeus lectins