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Adaption of human antibody ? and ? light chain architectures to CDR repertoires.


ABSTRACT: Monoclonal antibodies bind with high specificity to a wide range of diverse antigens, primarily mediated by their hypervariable complementarity determining regions (CDRs). The defined antigen binding loops are supported by the structurally conserved ?-sandwich framework of the light chain (LC) and heavy chain (HC) variable regions. The LC genes are encoded by two separate loci, subdividing the entity of antibodies into kappa (LC?) and lambda (LC?) isotypes that exhibit distinct sequence and conformational preferences. In this work, a diverse set of techniques were employed including machine learning, force field analysis, statistical coupling analysis and mutual information analysis of a non-redundant antibody structure collection. Thereby, it was revealed how subtle changes between the structures of LC? and LC? isotypes increase the diversity of antibodies, extending the predetermined restrictions of the general antibody fold and expanding the diversity of antigen binding. Interestingly, it was found that the characteristic framework scaffolds of ? and ? are stabilized by diverse amino acid clusters that determine the interplay between the respective fold and the embedded CDR loops. In conclusion, this work reveals how antibodies use the remarkable plasticity of the beta-sandwich Ig fold to incorporate a large diversity of CDR loops.

SUBMITTER: van der Kant R 

PROVIDER: S-EPMC6908821 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Adaption of human antibody λ and κ light chain architectures to CDR repertoires.

van der Kant Rob R   Bauer Joschka J   Karow-Zwick Anne R AR   Kube Sebastian S   Garidel Patrick P   Blech Michaela M   Rousseau Frederic F   Schymkowitz Joost J  

Protein engineering, design & selection : PEDS 20191201 3


Monoclonal antibodies bind with high specificity to a wide range of diverse antigens, primarily mediated by their hypervariable complementarity determining regions (CDRs). The defined antigen binding loops are supported by the structurally conserved β-sandwich framework of the light chain (LC) and heavy chain (HC) variable regions. The LC genes are encoded by two separate loci, subdividing the entity of antibodies into kappa (LCκ) and lambda (LCλ) isotypes that exhibit distinct sequence and conf  ...[more]

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