Modeling study of antibody combining sites to (α1-6)dextrans: Predictions of the conformational contribution of V(L)-CDR3 and J(κ) segments to groove-type combining sites Journal Article


Authors: Wang, D.; Hubbard, J. M.; Kabat, E. A.
Article Title: Modeling study of antibody combining sites to (α1-6)dextrans: Predictions of the conformational contribution of V(L)-CDR3 and J(κ) segments to groove-type combining sites
Abstract: The shuffling of the V(kappa)-Ox1 light chain joined to J(kappa)4 or J(kappa)5 instead of J(kappa)2 reduced or abolished antigen binding of three groove-type anti-(alpha1-6)dextran monoclonal antibodies, raising questions as to the structural roles of J(kappa) in antibody combining sites. The J(kappa)4 light chain used contains Pro95A at the V(kappa)-Ox1-J(kappa)4 junction, as well as a Phe to Ile substitution at the beginning of this J(kappa)4 segment. To predict whether the defect in antigen binding is a consequence of the J(kappa) replacement, the Pro insertion or the Phe to Ile substitution, model-building studies were performed. As shown by the surface representation of antibody combining sites, the models with length variation in the V(L)-CDR3 loop by only 1 residue altered the shape of the combining site dramatically; whereas those with replacement of J. or having amino acid substitutions in V(L)-CDR3 affect the combining site less extensively. A distinct loop configuration of V(L)-CDR3 appears in models having either a Pro, Gly, or Ala insertion at position 95A. These results indicate that the length of V(L)-CDR3 is crucial for its loop conformation and may, therefore, have played a major role in abolishing dextran binding activity of the J(kappa)4 variants. The potential of V(kappa)-Ox1 genes in generating conformational diversity in the loop of V(L)-CDR3 and its influence in forming different combining sites are discussed.
Keywords: genes; monoclonal-antibodies; specificity; binding; repertoire; complementarity; light-chains; heavy; hypervariable regions; alpha(1->6)dextran
Journal Title: Journal of Biological Chemistry
Volume: 268
Issue: 27
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 1993-09-25
Start Page: 20584
End Page: 20589
Language: English
ACCESSION: WOS:A1993LY01900095
PROVIDER: wos
PUBMED: 7690758
Notes: Article -- Source: Wos
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