View source for 7aqf


==Crystal Structure of Small Molecule Inhibitor TM5484 Bound to Stabilized Active Plasminogen Activator Inhibitor-1 (PAI-1-stab)==
<StructureSection load='7aqf' size='340' side='right'caption='[[7aqf]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7aqf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AQF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AQF FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.77&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RV2:5-Chloro-2-[[2-[3-(furan-3-yl)anilino]-2-oxoacetyl]amino]benzoic+acid'>RV2</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7aqf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aqf OCA], [https://pdbe.org/7aqf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aqf RCSB], [https://www.ebi.ac.uk/pdbsum/7aqf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aqf ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PAI1_HUMAN PAI1_HUMAN] Defects in SERPINE1 are the cause of plasminogen activator inhibitor-1 deficiency (PAI-1D) [MIM:[https://omim.org/entry/613329 613329]. It is a hematologic disorder characterized by increased bleeding after trauma, injury, or surgery. Affected females have menorrhagia. The bleeding defect is due to increased fibrinolysis of fibrin blood clots due to deficiency of plasminogen activator inhibitor-1, which inhibits tissue and urinary activators of plasminogen.<ref>PMID:9207454</ref>   Note=High concentrations of SERPINE1 seem to contribute to the development of venous but not arterial occlusions.
== Function ==
[https://www.uniprot.org/uniprot/PAI1_HUMAN PAI1_HUMAN] Serine protease inhibitor. This inhibitor acts as 'bait' for tissue plasminogen activator, urokinase, protein C and matriptase-3/TMPRSS7. Its rapid interaction with PLAT may function as a major control point in the regulation of fibrinolysis.<ref>PMID:15853774</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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 beta-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.

Structural Insight into the Two-Step Mechanism of PAI-1 Inhibition by Small Molecule TM5484.,Sillen M, Miyata T, Vaughan DE, Strelkov SV, Declerck PJ Int J Mol Sci. 2021 Feb 2;22(3). pii: ijms22031482. doi: 10.3390/ijms22031482. PMID:33540702<ref>PMID:33540702</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7aqf" style="background-color:#fffaf0;"></div>

==See Also==
*[[Plasminogen activator inhibitor|Plasminogen activator inhibitor]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Declerck PJ]]
[[Category: Sillen M]]
[[Category: Strelkov SV]]