6VVU

Anti-Tryptase fab E104.v1 bound to tryptase

6VVU の概要

• エントリーDOI: 10.2210/pdb6vvu/pdb
• 分子名称: Tryptase alpha/beta-1, Fab E104.v1 heavy chain, Fab E104.v1 light chain, ... (6 entities in total)
• 機能のキーワード: fab, inhibitor, tryptase, immune system, hydrolase-immune system complex, hydrolase/immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 315233.71

構造登録者

Ultsch, M.,Koerber, J.T. (登録日: 2020-02-18, 公開日: 2020-12-30, 最終更新日: 2024-11-06)

主引用文献

Maun, H.R.,Vij, R.,Walters, B.T.,Morando, A.,Jackman, J.K.,Wu, P.,Estevez, A.,Chen, X.,Franke, Y.,Lipari, M.T.,Dennis, M.S.,Kirchhofer, D.,Ciferri, C.,Loyet, K.M.,Yi, T.,Eigenbrot, C.,Lazarus, R.A.,Koerber, J.T.
Bivalent antibody pliers inhibit beta-tryptase by an allosteric mechanism dependent on the IgG hinge.
Nat Commun, 11:6435-6435, 2020

PubMed Abstract: Human β-tryptase, a tetrameric trypsin-like serine protease, is an important mediator of allergic inflammatory responses in asthma. Antibodies generally inhibit proteases by blocking substrate access by binding to active sites or exosites or by allosteric modulation. The bivalency of IgG antibodies can increase potency via avidity, but has never been described as essential for activity. Here we report an inhibitory anti-tryptase IgG antibody with a bivalency-driven mechanism of action. Using biochemical and structural data, we determine that four Fabs simultaneously occupy four exosites on the β-tryptase tetramer, inducing allosteric changes at the small interface. In the presence of heparin, the monovalent Fab shows essentially no inhibition, whereas the bivalent IgG fully inhibits β-tryptase activity in a hinge-dependent manner. Our results suggest a model where the bivalent IgG acts akin to molecular pliers, pulling the tetramer apart into inactive β-tryptase monomers, and may provide an alternative strategy for antibody engineering.

PubMed: 33353951
DOI: 10.1038/s41467-020-20143-x

実験手法

X-RAY DIFFRACTION (3 Å)