8C67

Crystal structure of Ab25 Fab

8C67 の概要

• エントリーDOI: 10.2210/pdb8c67/pdb
• 分子名称: antibody 25 heavy chain, antibody 25 light chain (3 entities in total)
• 機能のキーワード: antibody, fab-domain, igg, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 192555.08

構造登録者

Nyblom, M.,Izadi, A.,Tang, D.,Bahnan, W.,Happonen, L.,Malmstroem, J.,Shannon, O.,Malmstroem, L.,Nordenfelt, P. (登録日: 2023-01-11, 公開日: 2024-04-24, 最終更新日: 2026-03-04)

主引用文献

Izadi, A.,Karami, Y.,Bratanis, E.,Wrighton, S.,Khakzad, H.,Nyblom, M.,Olofsson, B.,Happonen, L.,Tang, D.,Sundwall, M.,Godzwon, M.,Chao, Y.,Toledo, A.G.,Schmidt, T.,Ohlin, M.,Nilges, M.,Malmstrom, J.,Bahnan, W.,Shannon, O.,Malmstrom, L.,Nordenfelt, P.
The hinge-engineered IgG1-IgG3 hybrid subclass IgGh 47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies.
Nat Commun, 15:3600-3600, 2024

PubMed Abstract: Streptococcus pyogenes can cause invasive disease with high mortality despite adequate antibiotic treatments. To address this unmet need, we have previously generated an opsonic IgG1 monoclonal antibody, Ab25, targeting the bacterial M protein. Here, we engineer the IgG2-4 subclasses of Ab25. Despite having reduced binding, the IgG3 version promotes stronger phagocytosis of bacteria. Using atomic simulations, we show that IgG3's Fc tail has extensive movement in 3D space due to its extended hinge region, possibly facilitating interactions with immune cells. We replaced the hinge of IgG1 with four different IgG3-hinge segment subclasses, IgGh. Hinge-engineering does not diminish binding as with IgG3 but enhances opsonic function, where a 47 amino acid hinge is comparable to IgG3 in function. IgGh shows improved protection against S. pyogenes in a systemic infection mouse model, suggesting that IgGh has promise as a preclinical therapeutic candidate. Importantly, the enhanced opsonic function of IgGh is generalizable to diverse S. pyogenes strains from clinical isolates. We generated IgGh versions of anti-SARS-CoV-2 mAbs to broaden the biological applicability, and these also exhibit strongly enhanced opsonic function compared to the IgG1 subclass. The improved function of the IgGh subclass in two distant biological systems provides new insights into antibody function.

PubMed: 38678029
DOI: 10.1038/s41467-024-47928-8

実験手法

X-RAY DIFFRACTION (1.88 Å)