ArticleProceedings of the National Academy of Sciences of the United States of America2016
Structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 91 citations in OpenAlex.
- A domain-swapped proPC1/3 structure reveals a conformational checkpoint for ER export.bioRxiv : the preprint server for biology · 2026Article
- Design, Synthesis, and Characterization of Dichlorobiphenyl-Derived Inhibitors of the Proprotein Convertase Furin.Journal of medicinal chemistry · 2025Article
- Beyond Processing: Furin as a Central Hub in Viral Pathogenesis and Genetic Susceptibility.Biomolecules · 2025Review
- Structural insights into proprotein convertase activation facilitate the engineering of highly specific furin inhibitors.Nature communications · 2025Article
- Molecular analysis of long COVID and new-onset diabetes mellitus: pathobiological relationships and current mechanistic views.Frontiers in endocrinology · 2025Review
- Structural insights into Furin enzyme inhibition to block SARS-CoV-2 spike protein cleavage: an in-silico approach.3 Biotech · 2024Article
- Evaluation of Potential Furin Protease Inhibitory Properties of Pioglitazone, Rosiglitazone, and Pirfenidone: An In Silico Docking and Molecular Dynamics Simulation Approach.Current issues in molecular biology · 2024Article
- The structure of immature tick-borne encephalitis virus supports the collapse model of flavivirus maturation.Science advances · 2024Article
- Promising Drug Fondaparinux for the Treatment of COVID-19: an In Silico Analysis of Low Molecular Weight Heparin, Direct Oral Anticoagulant, and Antiplatelet Drug Interactions with Host Protease Furin.Cardiovascular drugs and therapy · 2024Article
- Functional Roles of Furin in Cardio-Cerebrovascular Diseases.ACS pharmacology & translational science · 2024Review
- 1,25-Dihydroxyvitamin D3 regulates furin-mediated FGF23 cleavage.JCI insight · 2023Article
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- Study of protease-mediated processes initiating viral infection and cell-cell viral spreading of SARS-CoV-2.Journal of molecular modeling · 2022Article
- Dichlorophenylpyridine-Based Molecules Inhibit Furin through an Induced-Fit Mechanism.ACS chemical biology · 2022Article
- The Molecular Basis of FIX Deficiency in Hemophilia B.International journal of molecular sciences · 2022Review
- A Feasible Alternative Strategy Targeting Furin Disrupts SARS-CoV-2 Infection Cycle.Microbiology spectrum · 2022Article
- Spread of Gamma (P.1) Sub-Lineages Carrying Spike Mutations Close to the Furin Cleavage Site and Deletions in the N-Terminal Domain Drives Ongoing Transmission of SARS-CoV-2 in Amazonas, Brazil.Microbiology spectrum · 2022Article
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- 7,8-Dihydroxyflavone alleviates apoptosis and inflammation induced by retinal ischemia-reperfusion injury via activating TrkB/Akt/NF-kB signaling pathway.International journal of medical sciences · 2022Article
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Proprotein convertases (PCs) are highly specific proteases required for the proteolytic modification of many secreted proteins. An unbalanced activity of these enzymes is connected to pathologies like cancer, atherosclerosis, hypercholesterolaemia, and infectious diseases. Novel protein crystallographic structures of the prototypical PC family member furin in different functional states were determined to 1.8-2.0 Å. These, together with biochemical data and modeling by molecular dynamics calculations, suggest essential elements underlying its unusually high substrate specificity. Furin shows a complex activation mechanism and exists in at least four defined states: (i) the "off state," incompatible with substrate binding as seen in the unliganded enzyme; (ii) the active "on state" seen in inhibitor-bound furin; and the respective (iii) calcium-free and (iv) calcium-bound forms. The transition from the off to the on state is triggered by ligand binding at subsites S1 to S4 and appears to underlie the preferential recognition of the four-residue sequence motif of furin. The molecular dynamics simulations of the four structural states reflect the experimental observations in general and provide approximations of the respective stabilities. Ligation by calcium at the PC-specific binding site II influences the active-site geometry and determines the rotamer state of the oxyanion hole-forming Asn295, and thus adds a second level of the activity modulation of furin. The described crystal forms and the observations of different defined functional states may foster the development of new tools and strategies for pharmacological intervention targeting furin.
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