ArticleThe Journal of biological chemistry2014
Structure-function analyses of human kallikrein-related peptidase 2 establish the 99-loop as master regulator of activity.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 37 citations in OpenAlex.
- Modifications of the Prothrombin Active Site S4 Subpocket Confer Resistance to Dabigatran.Thrombosis and haemostasis · 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
- Structure-based identification of bioactive phytochemicals targeting kallikrein-related peptidase 2 for prostate cancer therapy.Frontiers in chemistry · 2025Article
- Remodelling of the tumour microenvironment by the kallikrein-related peptidases.Nature reviews. Cancer · 2022Review
- A Suite of Activity-Based Probes To Dissect the KLK Activome in Drug-Resistant Prostate Cancer.Journal of the American Chemical Society · 2021Article
- The Implications of Zinc Therapy in Combating the COVID-19 Global Pandemic.Journal of inflammation research · 2021Review
- From Plant to Patient: Thapsigargin, a Tool for Understanding Natural Product Chemistry, Total Syntheses, Biosynthesis, Taxonomy, ATPases, Cell Death, and Drug Development.Progress in the chemistry of organic natural products · 2021Article
- Review
- 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
- Interplay between conformational selection and zymogen activation.Scientific reports · 2018Article
- Engineered factor Xa variants retain procoagulant activity independent of direct factor Xa inhibitors.Nature communications · 2017Article
- Discovery of a novel conformational equilibrium in urokinase-type plasminogen activator.Scientific reports · 2017Article
- Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10.Biological chemistry · 2016Article
- Effects of Glycosylation on the Enzymatic Activity and Mechanisms of Proteases.International journal of molecular sciences · 2016Review
- Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics.Scientific reports · 2016Article
- Kallikreins - The melting pot of activity and function.Biochimie · 2016Review
- A Single Glycan at the 99-Loop of Human Kallikrein-related Peptidase 2 Regulates Activation and Enzymatic Activity.The Journal of biological chemistry · 2016Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human kallikrein-related peptidase 2 (KLK2) is a tryptic serine protease predominantly expressed in prostatic tissue and secreted into prostatic fluid, a major component of seminal fluid. Most likely it activates and complements chymotryptic KLK3 (prostate-specific antigen) in cleaving seminal clotting proteins, resulting in sperm liquefaction. KLK2 belongs to the "classical" KLKs 1-3, which share an extended 99- or kallikrein loop near their non-primed substrate binding site. Here, we report the 1.9 Å crystal structures of two KLK2-small molecule inhibitor complexes. In both structures discontinuous electron density for the 99-loop indicates that this loop is largely disordered. We provide evidence that the 99-loop is responsible for two biochemical peculiarities of KLK2, i.e. reversible inhibition by micromolar Zn(2+) concentrations and permanent inactivation by autocatalytic cleavage. Indeed, several 99-loop mutants of KLK2 displayed an altered susceptibility to Zn(2+), which located the Zn(2+) binding site at the 99-loop/active site interface. In addition, we identified an autolysis site between residues 95e and 95f in the 99-loop, whose elimination prevented the mature enzyme from limited autolysis and irreversible inactivation. An exhaustive comparison of KLK2 with related structures revealed that in the KLK family the 99-, 148-, and 220-loop exist in open and closed conformations, allowing or preventing substrate access, which extends the concept of conformational selection in trypsin-related proteases. Taken together, our novel biochemical and structural data on KLK2 identify its 99-loop as a key player in activity regulation.
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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.