ArticleJournal of molecular biology2012
A reverse binding motif that contributes to specific protease inhibition by antibodies.
Article in Journal of molecular biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 49 citations in OpenAlex.
- Enzymatic, structural, and biophysical characterization of a single-domain antibody (VHH) selectively and tightly inhibiting neutrophil elastase and exhibiting favorable developability properties.Protein science : a publication of the Protein Society · 2024Article
- Matriptase drives dissemination of ovarian cancer spheroids by a PAR-2/PI3K/Akt/MMP9 signaling axis.The Journal of cell biology · 2023Article
- Substrate derived sequences act as subsite-blocking motifs in protease inhibitory antibodies.Protein science : a publication of the Protein Society · 2023Article
- An MMP-9 exclusive neutralizing antibody attenuates blood-brain barrier breakdown in mice with stroke and reduces stroke patient-derived MMP-9 activity.Pharmacological research · 2023Article
- Novel Inhibitors and Activity-Based Probes Targeting Trypsin-Like Serine Proteases.Frontiers in chemistry · 2022Article
- Novel Ex Vivo Zymography Approach for Assessment of Protease Activity in Tissues with Activatable Antibodies.Pharmaceutics · 2021Article
- Structure of an affinity-matured inhibitory recombinant fab against urokinase plasminogen activator reveals basis of potency and specificity.Biochimica et biophysica acta. Proteins and proteomics · 2021Article
- Identification of recombinant Fabs for structural and functional characterization of HIV-host factor complexes.PloS one · 2021Article
- Generation of highly selective monoclonal antibodies inhibiting a recalcitrant protease using decoy designs.Biotechnology and bioengineering · 2020Article
- Protease Inhibition Mechanism of Camelid-like Synthetic Human Antibodies.Biochemistry · 2020Article
- Inhibitory antibodies identify unique sites of therapeutic vulnerability in rhinovirus and other enteroviruses.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Antibodies raised against a Sunn bug (Food science & nutrition · 2020Article
- Why recombinant antibodies - benefits and applications.Current opinion in biotechnology · 2019Review
- Cell surface-anchored serine proteases in cancer progression and metastasis.Cancer metastasis reviews · 2019Review
- Functional selection of protease inhibitory antibodies.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Membrane-Anchored Serine Proteases and Protease-Activated Receptor-2-Mediated Signaling: Co-Conspirators in Cancer Progression.Cancer research · 2019Review
- Blocking the proteolytic activity of zymogen matriptase with antibody-based inhibitors.The Journal of biological chemistry · 2019Article
- An unexpected switch in peptide binding mode: from simulation to substrate specificity.Journal of biomolecular structure & dynamics · 2018Article
- Selectivity Conversion of Protease Inhibitory Antibodies.Antibody therapeutics · 2018Article
- Engineering a potent inhibitor of matriptase from the natural hepatocyte growth factor activator inhibitor type-1 (HAI-1) protein.The Journal of biological chemistry · 2018Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
The type II transmembrane serine protease family consists of 18 closely related serine proteases that are implicated in multiple functions. To identify selective, inhibitory antibodies against one particular type II transmembrane serine protease, matriptase [MT-SP1 (membrane-type serine protease 1)], a phage display library was created with a natural repertoire of Fabs [fragment antigen binding (Fab)] from human naïve B cells. Fab A11 was identified with a 720 pM inhibition constant and high specificity for matriptase over other trypsin-fold serine proteases. A Trichoderma reesei system expressed A11 with a yield of ∼200 mg/L. The crystal structure of A11 in complex with matriptase has been determined and compared to the crystal structure of another antibody inhibitor (S4) in complex with matriptase. Previously discovered from a synthetic single-chain variable fragment library, S4 is also a highly selective and potent matriptase inhibitor. The crystal structures of the A11/matriptase and S4/matriptase complexes were solved to 2.1 Å and 1.5 Å, respectively. Although these antibodies, discovered from separate libraries, interact differently with the protease surface loops for their specificity, the structures reveal a similar novel mechanism of protease inhibition. Through the insertion of the H3 variable loop in a reverse orientation at the substrate-binding pocket, these antibodies bury a large surface area for potent inhibition and avoid proteolytic inactivation. This discovery highlights the critical role that the antibody scaffold plays in positioning loops to bind and inhibit protease function in a highly selective manner. Additionally, Fab A11 is a fully human antibody that specifically inhibits matriptase over other closely related proteases, suggesting that this approach could be useful for clinical applications.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.