9MNB
Beta1-tryptase monomer bound to inhibitory Fabs E82.AS and E104.v2
Summary for 9MNB
| Entry DOI | 10.2210/pdb9mnb/pdb |
| EMDB information | 48419 |
| Descriptor | Light chain of E104.v2 Fab, Tryptase alpha/beta-1, Heavy chain of E104v2 Fab, ... (6 entities in total) |
| Functional Keywords | serine protease, inhibitory antibodies, immune system, immune system-hydrolase complex, immune system/hydrolase |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 6 |
| Total formula weight | 130996.99 |
| Authors | |
| Primary citation | Maun, H.R.,Azumaya, C.M.,Walters, B.T.,Vij, R.,Morando, A.,Loyet, K.M.,Koerber, J.T.,Rohou, A.,Lazarus, R.A. Complete inhibition of beta-tryptase by tetramer dissociation and active site allostery due to a single antibody residue. Nat Commun, 17:-, 2026 Cited by PubMed Abstract: Human β-tryptase, a tetrameric trypsin-like serine protease, is an important mediator of inflammatory responses in asthma, allergy and other diseases. Here we report an anti-β-tryptase antibody with a superior mechanism of action compared to others since it not only inhibits tetrameric β-tryptase, but also completely inhibits monomeric β-tryptase activity. The antibody binds to an exosite that causes tetramer dissociation as either an IgG or Fab and, in addition, allosterically alters the substrate binding cleft on monomers, thus preventing substrate binding and proteolysis. We solve the cryoEM structure of the complex, generate biochemical data and engineer point mutations to elucidate the allosteric path of inhibition. This ultimately reveals a single Asp to Gly mutation in CDR-L3 that only slightly impacts binding affinity, but completely eliminates inhibitory activity. Finally, we improve antibody inhibitory potency up to 4.7-fold by structure-based design creating new charge-charge interactions. This antibody may have enhanced efficacy and potential to assess the relevance of β-tryptase, including monomers, in biological and clinical settings. PubMed: 41957026DOI: 10.1038/s41467-026-70491-3 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3 Å) |
Structure validation
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