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X-ray snapshots of the maturation of an antibody response to a protein antigen

Nature Structural & Molecular Biology volume 10, pages 482–488 (2003)Cite this article

Abstract

The process whereby the immune system generates antibodies of higher affinities during a response to antigen (affinity maturation) is a prototypical example of molecular evolution. Earlier studies have been confined to antibodies specific for small molecules (haptens) rather than for proteins. We compare the structures of four antibodies bound to the same site on hen egg white lysozyme (HEL) at different stages of affinity maturation. These X-ray snapshots reveal that binding is enhanced, not through the formation of additional hydrogen bonds or van der Waals contacts or by an increase in total buried surface, but by burial of increasing amounts of apolar surface at the expense of polar surface, accompanied by improved shape complementarity. The increase in hydrophobic interactions results from highly correlated rearrangements in antibody residues at the interface periphery, adjacent to the central energetic hot spot. This first visualization of the maturation of antibodies to protein provides insights into the evolution of high affinity in other protein–protein interfaces.

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Figure 1: Electron density (stereo views) in antibody combining sites.
Figure 2: Structure, sequence differences and binding energetics of antibody–HEL complexes.
Figure 3: Shape complementarity at antibody–HEL interfaces.
Figure 4: Conformational differences in antibody–HEL complexes.

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Acknowledgements

We thank M.K. Gilson, E.J. Sundberg and C.P. Swaminathan for critical reading of the manuscript. This work was supported by grants from the National Institutes of Health.

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Authors and Affiliations

  1. Center for Advanced Research in Biotechnology, W.M. Keck Laboratory for Structural Biology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, 20850, Maryland, USA

    Yili Li, Hongmin Li, Feng Yang & Roy A Mariuzza

  2. New York State Department of Health, Wadsworth Center, Empire State Plaza, P.O. Box 509, Albany, 12201, New York, USA

    Hongmin Li

  3. National Cancer Institute, Frederick Cancer Research and Development Center, P.O. Box B, Frederick, 21702-1201, Maryland, USA

    Sandra J Smith-Gill

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  1. Yili Li
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Correspondence to Roy A Mariuzza.

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Li, Y., Li, H., Yang, F. et al. X-ray snapshots of the maturation of an antibody response to a protein antigen. Nat Struct Mol Biol 10, 482–488 (2003). https://doi.org/10.1038/nsb930

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