6O1F

Complex between soybean trypsin inhibitor beta1-tryptase and a humanized fab

Summary for 6O1F

• Entry DOI: 10.2210/pdb6o1f/pdb
• Related: 4a6l
• Descriptor: Tryptase alpha/beta-1, Heavy Chain hu31A.v11, Trypsin inhibitor A, ... (6 entities in total)
• Functional Keywords: antibody, fab, tryptase, inhibitor, immune system, immune system-hydrolase complex, immune system/hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 98476.37

Authors

Ultsch, M.H.,Yi, T. (deposition date: 2019-02-19, release date: 2019-10-16, Last modification date: 2024-10-23)

Primary citation

Maun, H.R.,Jackman, J.K.,Choy, D.F.,Loyet, K.M.,Staton, T.L.,Jia, G.,Dressen, A.,Hackney, J.A.,Bremer, M.,Walters, B.T.,Vij, R.,Chen, X.,Trivedi, N.N.,Morando, A.,Lipari, M.T.,Franke, Y.,Wu, X.,Zhang, J.,Liu, J.,Wu, P.,Chang, D.,Orozco, L.D.,Christensen, E.,Wong, M.,Corpuz, R.,Hang, J.Q.,Lutman, J.,Sukumaran, S.,Wu, Y.,Ubhayakar, S.,Liang, X.,Schwartz, L.B.,Babina, M.,Woodruff, P.G.,Fahy, J.V.,Ahuja, R.,Caughey, G.H.,Kusi, A.,Dennis, M.S.,Eigenbrot, C.,Kirchhofer, D.,Austin, C.D.,Wu, L.C.,Koerber, J.T.,Lee, W.P.,Yaspan, B.L.,Alatsis, K.R.,Arron, J.R.,Lazarus, R.A.,Yi, T.
An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma.
Cell, 179:417-431.e19, 2019

PubMed Abstract: Severe asthma patients with low type 2 inflammation derive less clinical benefit from therapies targeting type 2 cytokines and represent an unmet need. We show that mast cell tryptase is elevated in severe asthma patients independent of type 2 biomarker status. Active β-tryptase allele count correlates with blood tryptase levels, and asthma patients carrying more active alleles benefit less from anti-IgE treatment. We generated a noncompetitive inhibitory antibody against human β-tryptase, which dissociates active tetramers into inactive monomers. A 2.15 Å crystal structure of a β-tryptase/antibody complex coupled with biochemical studies reveal the molecular basis for allosteric destabilization of small and large interfaces required for tetramerization. This anti-tryptase antibody potently blocks tryptase enzymatic activity in a humanized mouse model, reducing IgE-mediated systemic anaphylaxis, and inhibits airway tryptase in Ascaris-sensitized cynomolgus monkeys with favorable pharmacokinetics. These data provide a foundation for developing anti-tryptase as a clinical therapy for severe asthma.

PubMed: 31585081
DOI: 10.1016/j.cell.2019.09.009

Experimental method

X-RAY DIFFRACTION (2.15 Å)