7AQF

Crystal Structure of Small Molecule Inhibitor TM5484 Bound to Stabilized Active Plasminogen Activator Inhibitor-1 (PAI-1-stab)

Summary for 7AQF

• Entry DOI: 10.2210/pdb7aqf/pdb
• Descriptor: Plasminogen activator inhibitor 1, 5-Chloro-2-[[2-[3-(furan-3-yl)anilino]-2-oxoacetyl]amino]benzoic acid (3 entities in total)
• Functional Keywords: plasminogen activator inhibitor-1, pai-1, pai-1-stab, serpin, protease inhibitor, serine protease inhibitor, small molecule inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 85886.79

Authors

Sillen, M.,Strelkov, S.V.,Declerck, P.J. (deposition date: 2020-10-21, release date: 2021-02-17, Last modification date: 2024-01-31)

Primary citation

Sillen, M.,Miyata, T.,Vaughan, D.E.,Strelkov, S.V.,Declerck, P.J.
Structural Insight into the Two-Step Mechanism of PAI-1 Inhibition by Small Molecule TM5484.
Int J Mol Sci, 22:-, 2021

PubMed 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.

PubMed: 33540702
DOI: 10.3390/ijms22031482

Experimental method

X-RAY DIFFRACTION (1.77 Å)