ジャーナル: Nat Commun / 年: 2020 タイトル: Bivalent antibody pliers inhibit β-tryptase by an allosteric mechanism dependent on the IgG hinge. 著者: Henry R Maun / Rajesh Vij / Benjamin T Walters / Ashley Morando / Janet K Jackman / Ping Wu / Alberto Estevez / Xiaocheng Chen / Yvonne Franke / Michael T Lipari / Mark S Dennis / Daniel ...著者: Henry R Maun / Rajesh Vij / Benjamin T Walters / Ashley Morando / Janet K Jackman / Ping Wu / Alberto Estevez / Xiaocheng Chen / Yvonne Franke / Michael T Lipari / Mark S Dennis / Daniel Kirchhofer / Claudio Ciferri / Kelly M Loyet / Tangsheng Yi / Charles Eigenbrot / Robert A Lazarus / James T Koerber / 要旨: 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 ...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.
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A: Tryptase alpha/beta-1 B: Tryptase alpha/beta-1 D: Tryptase alpha/beta-1 C: Tryptase alpha/beta-1 E: Fab E104.v1 heavy chain F: Fab E104.v1 light chain G: Fab E104.v1 heavy chain H: Fab E104.v1 heavy chain I: Fab E104.v1 light chain J: Fab E104.v1 heavy chain K: Fab E104.v1 light chain L: Fab E104.v1 light chain ヘテロ分子