ArticleInternational journal of molecular sciences2021
Structural Insight into the Two-Step Mechanism of PAI-1 Inhibition by Small Molecule TM5484.
Article in International journal of molecular sciences, 2021. 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.
- A randomized double-blind placebo-controlled trial of an inhibitor of plasminogen activator inhibitor-1 (TM5614) in mild to moderate COVID-19.Scientific reports · 2024Trial
- Review
- Aptamer-mediated modulation of PAI-1 function reveals a novel mechanism for restoring fibrinolytic balance.NAR molecular medicine · 2026Article
- Plasminogen Activator Inhibitor-1 Mediates Tolerance to Anti-PD-1 Immunotherapy in Non-Small Cell Lung Cancer.Molecular cancer therapeutics · 2026Article
- The expanding landscape of adipokines: emerging roles of PAI-1 and vaspin in cardiometabolic diseases.Frontiers in endocrinology · 2026Review
- INHIBITING THE INHIBITOR: WOULD TARGETING PAI-1 RESULT IN A LOW-DOSE, WELL-TOLERATED TREATMENT OF EMPYEMA?Biomedical sciences instrumentation · 2025Article
- A Contemporary Review of Plasminogen Activator Inhibitor Type 1: Structure, Function, Genetic Architecture, and Intracellular/Extracellular Roles.TH open : companion journal to thrombosis and haemostasis · 2025Review
- Serum Plasminogen Activator Inhibitor-1, α 1-Acid Glycoprotein, C-Reactive Protein, and Platelet Factor 4 Levels-Promising Molecules That Can Complete the "Puzzle" of the Biochemical Milieu in Severe Burns: Preliminary Results of a Cohort Prospective Study.Journal of clinical medicine · 2024Article
- Recent advancement of novel marine fungi derived secondary metabolite fibrinolytic compound FGFC in biomedical applications: a review.Frontiers in cellular and infection microbiology · 2024Review
- Novel Function of Cancer Stem Cell Marker ALDH1A3 in Glioblastoma: Pro-Angiogenesis through Paracrine PAI-1 and IL-8.Cancers · 2023Article
- Suppression of antitumor cytokine IL‑24 by PRG4 and PAI‑1 may promote myxoid liposarcoma cell survival.Biomedical reports · 2023Article
- Review
- Identification and validation ofFrontiers in pharmacology · 2023Article
- Network pharmacology and bioinformatics were used to construct a prognostic model and immunoassay of core target genes in the combination of quercetin and kaempferol in the treatment of colorectal cancer.Journal of Cancer · 2023Article
- Plasma biomarkers associated with survival and thrombosis in hospitalized COVID-19 patients.International journal of hematology · 2022Article
- Network Pharmacology and Molecular Docking Elucidate the Underlying Pharmacological Mechanisms of the HerbViruses · 2022Article
- The Fibrinolytic System: Mysteries and Opportunities.HemaSphere · 2021Review
- A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: To Target or Not to Target?International journal of molecular sciences · 2021Review
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5 authors.
Funding
Abstract
Plasminogen activator inhibitor-1 (PAI-1), a key regulator of the fibrinolytic system, is the main physiological inhibitor of plasminogen activators. By interacting with matrix components, including vitronectin (Vn), PAI-1 plays a regulatory role in tissue remodeling, cell migration, and intracellular signaling. Emerging evidence points to a role for PAI-1 in various pathological conditions, including cardiovascular diseases, cancer, and fibrosis. Targeting PAI-1 is therefore a promising therapeutic strategy in PAI-1-related pathologies. A class of small molecule inhibitors including TM5441 and TM5484, designed to bind the cleft in the central β-sheet A of PAI-1, showed to be potent PAI-1 inhibitors in vivo. However, their binding site has not yet been confirmed. Here, we report two X-ray crystallographic structures of PAI-1 in complex with TM5484. The structures revealed a binding site at the flexible joint region, which is distinct from the presumed binding site. Based on the structural analysis and biochemical data we propose a mechanism for the observed dose-dependent two-step mechanism of PAI-1 inhibition. By binding to the flexible joint region in PAI-1, TM5484 might restrict the structural flexibility of this region, thereby inducing a substrate form of PAI-1 followed by a conversion to an inert form.
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