7aqf Citations

Structural Insight into the Two-Step Mechanism of PAI-1 Inhibition by Small Molecule TM5484.

OpenAccess logo Int J Mol Sci 22 (2021)
Cited: 13 times
EuropePMC logo PMID: 33540702

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.

Articles - 7aqf mentioned but not cited (4)



Reviews citing this publication (3)

  1. A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: To Target or Not to Target? Sillen M, Declerck PJ. Int J Mol Sci 22 2721 (2021)
  2. The Fibrinolytic System: Mysteries and Opportunities. Medcalf RL, Keragala CB. Hemasphere 5 e570 (2021)
  3. The Role of the Plasminogen/Plasmin System in Inflammation of the Oral Cavity. Yatsenko T, Skrypnyk M, Troyanovska O, Tobita M, Osada T, Takahashi S, Hattori K, Heissig B. Cells 12 445 (2023)

Articles citing this publication (6)

  1. Plasma biomarkers associated with survival and thrombosis in hospitalized COVID-19 patients. Cabrera-Garcia D, Miltiades A, Yim P, Parsons S, Elisman K, Mansouri MT, Wagener G, Harrison NL. Int J Hematol 116 937-946 (2022)
  2. A randomized double-blind placebo-controlled trial of an inhibitor of plasminogen activator inhibitor-1 (TM5614) in mild to moderate COVID-19. Hirai T, Asano K, Ito I, Miyazaki Y, Sugiura H, Agirbasli M, Kobayashi S, Kobayashi M, Shimada D, Natsume I, Kawasaki T, Ohba T, Tajiri S, Sakamaki F, Mineshita M, Takihara T, Sekiya K, Tomii K, Tomioka H, Kita H, Nishizaka Y, Fukui M, Miyata T, Harigae H. Sci Rep 14 165 (2024)
  3. Identification and validation of SERPINE1 as a prognostic and immunological biomarker in pan-cancer and in ccRCC. Li L, Li F, Xu Z, Li L, Hu H, Li Y, Yu S, Wang M, Gao L. Front Pharmacol 14 1213891 (2023)
  4. 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. Gu C, Tang L, Hao Y, Dong S, Shen J, Xie F, Han Z, Luo W, He J, Yu L. J Cancer 14 1956-1980 (2023)
  5. Novel Function of Cancer Stem Cell Marker ALDH1A3 in Glioblastoma: Pro-Angiogenesis through Paracrine PAI-1 and IL-8. Chen Z, Will R, Kim SN, Busch MA, Dünker N, Dammann P, Sure U, Zhu Y. Cancers (Basel) 15 4422 (2023)
  6. Suppression of antitumor cytokine IL‑24 by PRG4 and PAI‑1 may promote myxoid liposarcoma cell survival. Oikawa K, Kuroda M, Ehata S. Biomed Rep 19 60 (2023)