7AQG
Crystal Structure of Small Molecule Inhibitor TM5484 Bound to Stabilized Active Plasminogen Activator Inhibitor-1 (PAI-1-W175F)
Summary for 7AQG
| Entry DOI | 10.2210/pdb7aqg/pdb |
| Descriptor | Plasminogen activator inhibitor 1, VHH-2g-42 (Nb42), VHH-2w-64 (Nb64), ... (5 entities in total) |
| Functional Keywords | plasminogen activator inhibitor-1, pai-1, pai-1-w175f, serpin, protease inhibitor, serine protease inhibitor, small molecule, antibody fragments, nanobodies, protein complex, hydrolase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 69004.44 |
| Authors | Sillen, M.,Strelkov, S.V.,Declerck, P.J. (deposition date: 2020-10-21, release date: 2021-02-24, Last modification date: 2024-11-20) |
| 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 Cited by 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: 33540702DOI: 10.3390/ijms22031482 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.27 Å) |
Structure validation
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