Do antibody CDR loops change conformation upon binding?
Chu'nan Liu1, Lilian M Denzler1, Oliver E C Hood1
1Structural and Molecular Biology, Division of Biosciences, University College London, London, UK.
Mabs
|March 13, 2024
Summary
Antibody drug development requires understanding antigen binding. This study analyzed antibody structures, finding complementarity-determining regions (CDRs) show minimal conformational change upon binding, except for CDR-H3.
Area of Science:
- Structural biology
- Immunology
- Computational chemistry
Background:
- Antibodies are crucial therapeutics, with over 100 licensed drugs.
- Modifying antibody affinity necessitates understanding antibody-antigen interactions.
- The conformational changes of complementarity-determining regions (CDRs) upon antigen binding remain an open question.
Purpose of the Study:
- To conduct a large-scale survey of CDR conformational changes during antibody-antigen binding.
- To analyze the impact of antigen binding on antibody CDR structures.
- To provide data for improving antibody modeling and drug design.
Main Methods:
- Compiled a dataset (AbAgDb) of 177 antibodies with both bound and unbound structures from the Protein Data Bank.
- Analyzed Cα backbone conformational changes in CDRs using RMSD analysis.
- Compared bound CDR conformations with the conformational space of unbound CDRs.
Main Results:
- Most CDRs, excluding CDR-H3, exhibit minimal conformational changes upon antigen binding.
- 70.6% and 87% of CDR-H3s showed global Cα RMSD ≤ 1.0Å and ≤ 2.0Å, respectively.
- The majority of bound CDR conformations were found within the conformational space of unbound CDRs.
Conclusions:
- Antibody CDRs, particularly CDR-H3, undergo limited conformational adjustments when binding antigens.
- Existing unbound CDR conformational data adequately represents bound states for most CDRs.
- Findings will inform antibody modeling, docking strategies, and drug development.
Keywords:
CDR flexibilityCDRsantibodiesantibody bindingantibody structurecomplementarity determining regionsMore Related Videos
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