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TitleBivalent antibody pliers inhibit β-tryptase by an allosteric mechanism dependent on the IgG hinge.
Journal, issue, pagesNat Commun, Vol. 11, Issue 1, Page 6435, Year 2020
Publish dateDec 22, 2020
AuthorsHenry 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 /
PubMed AbstractHuman 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.
External linksNat Commun / PubMed:33353951 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution3 - 15.0 Å
Structure data

EMDB-21389:
Negative Staining Reconstruction of Tryptase Tetramer bound to E104 Fab
Method: EM (single particle) / Resolution: 15.0 Å

PDB-6vvu:
Anti-Tryptase fab E104.v1 bound to tryptase
Method: X-RAY DIFFRACTION / Resolution: 3.0 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-0GJ:
L-alpha-glutamyl-N-{(1S)-4-{[amino(iminio)methyl]amino}-1-[(1S)-2-chloro-1-hydroxyethyl]butyl}glycinamide

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
KeywordsHYDROLASE/IMMUNE SYSTEM / Fab / inhibitor / tryptase / IMMUNE SYSTEM / HYDROLASE-IMMUNE SYSTEM complex

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