Conformational features and interaction mechanisms of VHH antibodies with β-hairpin-like CDR-H3: A case of Nb8-HigB2 interaction.
Yamamoto, K.; Nagatoishi, S.; Nakakido, M.; Kuroda, D.; Tsumoto, K.
Show abstract
{beta}-hairpin conformation is regarded as an important basic motif to form and regulate protein-protein interactions. Single-domain VHH antibodies are potential therapeutic and diagnostic tools, and the third complementarity-determining regions of the heavy chains (CDR-H3s) of these antibodies are critical for antigen recognition. Although the sequences and conformations of the CDR-H3s are diverse, CDR-H3s sometimes adopt {beta}-hairpin-like conformations. However, characteristic features and interaction mechanisms of {beta}-hairpin-like CDR-H3s remain to be fully elucidated. In this study, we investigated the molecular recognition of the anti-HigB2 VHH antibody Nb8, which has a CDR-H3 that forms a {beta}-hairpin-like conformation. The interaction was analyzed by evaluation of alanine-scanning mutants, molecular dynamics simulations, and hydrogen/deuterium exchange mass spectrometry. These experiments demonstrated that positions 93 and 94 (Chothia numbering) in framework region 3, which is right outside CDR-H3 by definition, play pivotal roles in maintaining structural stability and binding properties of Nb8. These findings will facilitate design and optimization of single-domain antibodies.
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