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The origin of CDR H3 structural diversity
Brian D Weitzner1, Roland L Dunbrack2, Jeffrey J Gray3
1Department of Chemical & Biomolecular Engineering, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
The antibody's H3 loop kink, previously unclassified, is common in other proteins. This structural feature disrupts beta-strand pairing, driving H3 loop diversity in adaptive immunity.
Area of Science:
- Immunology
- Structural Biology
- Protein Science
Background:
- Antibody complementarity determining region (CDR) H3 loops are crucial for adaptive immunity.
- Unlike other CDR loops, H3 loop conformations are unclassifiable, often featuring a C-terminal kink.
Purpose of the Study:
- Investigate the prevalence and function of the H3 loop kink in antibodies.
- Determine if similar loop structures exist in non-antibody proteins.
Main Methods:
- Searched 15,679 non-antibody protein structures for geometric similarity to antibody H3 loop regions, including the kink.
- Identified and analyzed H3-like loops across various protein families.
Main Results:
- Discovered 1,030 H3-like loops in 632 protein families, with some, like PDZ domains, utilizing these regions for binding.
- The H3 loop kink was found to disrupt beta-strand pairing at the loop's base.
Conclusions:
- The H3 loop kink is conserved in immunoglobulin heavy chain folds due to its role in disrupting beta-strand pairing.
- This kink is a key factor driving the structural diversity observed in CDR H3 loops, impacting adaptive immunological functions.
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