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Antibody-antigen interactions: contact analysis and binding site topography
R M MacCallum1, A C Martin, J M Thornton
1Department of Biochemistry and Molecular Biology, University College London, UK.
Journal of Molecular Biology
|October 11, 1996
Summary
This study redefines antibody complementarity determining regions (CDRs) by analyzing antigen contacts from crystal structures. It also classifies antibody combining site shapes, aiding antibody engineering and antigen docking.
Area of Science:
- Structural biology
- Immunology
- Biophysics
Background:
- Antibody structure-function relationships are crucial for immunology and biotechnology.
- Understanding antibody-antigen interactions informs antibody engineering and drug development.
- Existing definitions of complementarity determining regions (CDRs) may not fully capture antigen contact dynamics.
Purpose of the Study:
- To analyze antigen-contacting residues and combining site shape in antibody Fv and Fab crystal structures.
- To propose a new definition for CDRs based on observed antigen contacts.
- To classify antibody combining site topography and its changes upon antigen binding.
Main Methods:
- Analysis of antigen-contacting residues in antibody Fv and Fab crystal structures from the Protein Data Bank.
- Calculation of antigen-contacting propensities for each antibody residue.
- Development and application of an objective method for classifying protein surface topography, specifically antibody combining sites.
- Clustering of antibody combining site surfaces into four topographic classes: concave, moderately concave, ridged, and planar.
- Determination of topographic classes for ten pairs of complexed and uncomplexed antibody-antigen crystal structures.
Main Results:
- Antigen contacts are more frequent at central CDR residues; some peripheral CDR residues contact only large antigens.
- Non-contacting CDR residues align with those defining canonical conformations.
- Four topographic classes of antibody combining sites were identified: concave, moderately concave, ridged, and planar.
- Four out of ten antibody-antigen complexes showed a change in topographic class upon binding.
Conclusions:
- A new definition of CDRs based on direct antigen contacts can be proposed.
- Antibody combining site topography correlates with antigen type (hapten, peptide, protein).
- Changes in topography upon complexation are observed, impacting binding site characterization.
- The findings are applicable to antibody engineering, antigen docking, and clinical immunology, including locating antigen-binding pockets.