ArticleScientific reports2016
Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- HFGuidedDesign:Chemical science · 2026Article
- Drug Discovery Strategies for Kallikrein-Related Peptidases.International journal of molecular sciences · 2025Review
- Prostate cancer risk-associated single-nucleotide polymorphisms impact the conformational dynamics of prostate-specific antigen.BMC biology · 2025Article
- Allosteric Anti-KLK4 Antibody Development for Targeted Anti-cancer Effects in Ovarian Carcinoma.Journal of molecular biology · 2025Article
- HighFold: accurately predicting structures of cyclic peptides and complexes with head-to-tail and disulfide bridge constraints.Briefings in bioinformatics · 2024Article
- Remodelling of the tumour microenvironment by the kallikrein-related peptidases.Nature reviews. Cancer · 2022Review
- A KLK4 proteinase substrate capture approach to antagonize PAR1.Scientific reports · 2021Article
- Structural studies of complexes of kallikrein 4 with wild-type and mutated forms of the Kunitz-type inhibitor BbKI.Acta crystallographica. Section D, Structural biology · 2021Article
- Bowman-Birk Inhibitors: Insights into Family of Multifunctional Proteins and Peptides with Potential Therapeutical Applications.Pharmaceuticals (Basel, Switzerland) · 2020Review
- NBCZone: Universal three-dimensional construction of eleven amino acids near the catalytic nucleophile and base in the superfamily of (chymo)trypsin-like serine fold proteases.International journal of biological macromolecules · 2020Article
- Review
- A protein scaffold, engineered SPINK2, for generation of inhibitors with high affinity and specificity against target proteases.Scientific reports · 2019Article
- Crystal structure of the inhibitor-free form of the serine protease kallikrein-4.Acta crystallographica. Section F, Structural biology communications · 2019Article
- Crystal structures of the complex of a kallikrein inhibitor from Bauhinia bauhinioides with trypsin and modeling of kallikrein complexes.Acta crystallographica. Section D, Structural biology · 2019Article
- Potent, Selective, and Cell-Penetrating Inhibitors of Kallikrein-Related Peptidase 4 Based on the Cyclic Peptide MCoTI-II.ACS medicinal chemistry letters · 2018Article
- An unexpected switch in peptide binding mode: from simulation to substrate specificity.Journal of biomolecular structure & dynamics · 2018Article
- Structural determinants of specificity and regulation of activity in the allosteric loop network of human KLK8/neuropsin.Scientific reports · 2018Article
- Understanding Russell's viper venom factor V activator's substrate specificity by surface plasmon resonance and in-silico studies.PloS one · 2017Article
Corrections and comments
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (~1 Å) resolution, as well as with bound nickel. These structures offer a structural rationalization for the potency and selectivity of these inhibitors, and together with MD simulation and computational analysis, reveal a dynamic pathway between the metal binding exosite and the active site, providing key details of a previously proposed allosteric mode of inhibition. Collectively, this work provides insight into both direct and indirect mechanisms of inhibition for KLK4 that have broad implications for the enzymology of the serine protease superfamily, and may potentially be exploited for the design of therapeutic inhibitors.
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