ArticleThe Biochemical journal2011
The P(2)' residue is a key determinant of mesotrypsin specificity: engineering a high-affinity inhibitor with anticancer activity.
Article in The Biochemical journal, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 41 citations in OpenAlex.
- Discovery of an autoinhibited conformation in mesotrypsin reveals a strategy for selective serine protease inhibition.Science advances · 2025Article
- Improvement in XIa Selectivity of Snake Venom Peptide Analogue BF9-N17K Using P2' Amino Acid Replacements.Toxins · 2025Article
- Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers.Molecular oncology · 2023Article
- SAXS Analysis and Characterization of Anticancer Activity of PNP-UDP Family Protein from Putranjiva roxburghii.The protein journal · 2022Article
- Serine Protease 3 Promotes Progression of Diffuse Large B-Cell Lymphoma and Serves as a Novel Prognostic Predictor.Disease markers · 2022Article
- Climbing Up and Down Binding Landscapes through Deep Mutational Scanning of Three Homologous Protein-Protein Complexes.Journal of the American Chemical Society · 2021Article
- Avidity observed between a bivalent inhibitor and an enzyme monomer with a single active site.PloS one · 2021Article
- Disulfide engineering of human Kunitz-type serine protease inhibitors enhances proteolytic stability and target affinity toward mesotrypsin.The Journal of biological chemistry · 2019Article
- PRSS3/Mesotrypsin and kallikrein-related peptidase 5 are associated with poor prognosis and contribute to tumor cell invasion and growth in lung adenocarcinoma.Scientific reports · 2019Article
- Mapping protein selectivity landscapes using multi-target selective screening and next-generation sequencing of combinatorial libraries.Nature communications · 2018Article
- A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering.The Journal of biological chemistry · 2018Article
- Pre-equilibrium competitive library screening for tuning inhibitor association rate and specificity toward serine proteases.The Biochemical journal · 2018Article
- Article
- An Acrobatic Substrate Metamorphosis Reveals a Requirement for Substrate Conformational Dynamics in Trypsin Proteolysis.The Journal of biological chemistry · 2016Article
- Combinatorial protein engineering of proteolytically resistant mesotrypsin inhibitors as candidates for cancer therapy.The Biochemical journal · 2016Article
- Mesotrypsin Has Evolved Four Unique Residues to Cleave Trypsin Inhibitors as Substrates.The Journal of biological chemistry · 2015Article
- Mesotrypsin Signature Mutation in a Chymotrypsin C (CTRC) Variant Associated with Chronic Pancreatitis.The Journal of biological chemistry · 2015Article
- Three-dimensional Structure of a Kunitz-type Inhibitor in Complex with an Elastase-like Enzyme.The Journal of biological chemistry · 2015Article
- Sequence and conformational specificity in substrate recognition: several human Kunitz protease inhibitor domains are specific substrates of mesotrypsin.The Journal of biological chemistry · 2014Article
- Recent advances on plasmin inhibitors for the treatment of fibrinolysis-related disorders.Medicinal research reviews · 2014Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
PRSS3/mesotrypsin is an atypical isoform of trypsin, the up-regulation of which has been implicated in promoting tumour progression. Mesotrypsin inhibitors could potentially provide valuable research tools and novel therapeutics, but small-molecule trypsin inhibitors have low affinity and little selectivity, whereas protein trypsin inhibitors bind poorly and are rapidly degraded by mesotrypsin. In the present study, we use mutagenesis of a mesotrypsin substrate, APPI (amyloid precursor protein Kunitz protease inhibitor domain), and of a poor mesotrypsin inhibitor, BPTI (bovine pancreatic trypsin inhibitor), to dissect mesotrypsin specificity at the key P(2)' position. We find that bulky and charged residues strongly disfavour binding, whereas acidic residues facilitate catalysis. Crystal structures of mesotrypsin complexes with BPTI variants provide structural insights into mesotrypsin specificity and inhibition. Through optimization of the P(1) and P(2)' residues of BPTI, we generate a stable high-affinity mesotrypsin inhibitor with an equilibrium binding constant K(i) of 5.9 nM, a >2000-fold improvement in affinity over native BPTI. Using this engineered inhibitor, we demonstrate the efficacy of pharmacological inhibition of mesotrypsin in assays of breast cancer cell malignant growth and pancreatic cancer cell invasion. Although further improvements in inhibitor selectivity will be important before clinical potential can be realized, the results of the present study support the feasibility of engineering protein protease inhibitors of mesotrypsin and highlight their therapeutic potential.
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