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. 1989 Jul;86(14):5532–5536. doi: 10.1073/pnas.86.14.5532

Significant structural and functional change of an antigen-binding site by a distant amino acid substitution: proposal of a structural mechanism.

N C Chien 1, V A Roberts 1, A M Giusti 1, M D Scharff 1, E D Getzoff 1
PMCID: PMC297657  PMID: 2748602

Abstract

To study the molecular basis for antibody diversity and the structural basis for antigen binding, we have characterized the loss of phosphocholine (P-Cho) binding both experimentally and computationally in U10, a somatic mutant of the antibody S107. Nucleotide sequencing of U10 shows a single base change in JH1, substituting Asp-101 with Ala, over 9 A distant from the P-Cho-binding pocket. Probing with antiidiotypic antibodies suggests local, not global, conformational changes. Computational results support a specific structural mechanism for the loss of P-Cho binding. The U10 mutation eliminates the charged interaction between Asp-101 and Arg-94, which allows the Arg-94 side chain to disrupt P-Cho binding sterically and electrostatically by folding into the P-Cho-binding site. These results specifically show the importance of the Arg-94 to Asp-101 side chain salt bridge in the heavy-chain CDR3 conformation and suggest that residues distant from the binding site play an important role in antibody diversity and inducible complementarity.

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Selected References

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