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4g8r

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==Crystal Structure of a novel small molecule inactivator bound to plasminogen activator inhibitor-1==
==Crystal Structure of a novel small molecule inactivator bound to plasminogen activator inhibitor-1==
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<StructureSection load='4g8r' size='340' side='right' caption='[[4g8r]], [[Resolution|resolution]] 2.19&Aring;' scene=''>
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<StructureSection load='4g8r' size='340' side='right'caption='[[4g8r]], [[Resolution|resolution]] 2.19&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4g8r]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G8R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G8R FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4g8r]] 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=4G8R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G8R FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=96P:(2S)-3-({[3-(TRIFLUOROMETHYL)PHENOXY]CARBONYL}AMINO)PROPANE-1,2-DIYL+BIS(3,4,5-TRIHYDROXYBENZOATE)'>96P</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.19&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1b3k|1b3k]], [[4g8o|4g8o]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=96P:(2S)-3-({[3-(TRIFLUOROMETHYL)PHENOXY]CARBONYL}AMINO)PROPANE-1,2-DIYL+BIS(3,4,5-TRIHYDROXYBENZOATE)'>96P</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PAI-1, PAI1, PLANH1, SERPINE1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4g8r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g8r OCA], [https://pdbe.org/4g8r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g8r RCSB], [https://www.ebi.ac.uk/pdbsum/4g8r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g8r ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4g8r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g8r OCA], [http://pdbe.org/4g8r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4g8r RCSB], [http://www.ebi.ac.uk/pdbsum/4g8r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4g8r ProSAT]</span></td></tr>
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</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/PAI1_HUMAN PAI1_HUMAN]] Defects in SERPINE1 are the cause of plasminogen activator inhibitor-1 deficiency (PAI-1D) [MIM:[http://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.
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[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 ==
== Function ==
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[[http://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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Plasminogen activator inhibitor type-1 (PAI-1) is a member of the serine protease inhibitor (serpin) family. Excessive PAI-1 activity is associated with human disease, making it an attractive pharmaceutical target. However, like other serpins, PAI-1 has a labile structure, making it a difficult target for the development of small molecule inhibitors, and to date, there are no US Food and Drug Administration-approved small molecule inactivators of any serpins. Here we describe the mechanistic and structural characterization of a high affinity inactivator of PAI-1. This molecule binds to PAI-1 reversibly and acts through an allosteric mechanism that inhibits PAI-1 binding to proteases and to its cofactor vitronectin. The binding site is identified by X-ray crystallography and mutagenesis as a pocket at the interface of beta-sheets B and C and alpha-helix H. A similar pocket is present on other serpins, suggesting that this site could be a common target in this structurally conserved protein family.
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Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1.,Li SH, Reinke AA, Sanders KL, Emal CD, Whisstock JC, Stuckey JA, Lawrence DA Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):E4941-9. doi:, 10.1073/pnas.1216499110. Epub 2013 Dec 2. PMID:24297881<ref>PMID:24297881</ref>
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==See Also==
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*[[Plasminogen activator inhibitor|Plasminogen activator inhibitor]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4g8r" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Lawrence, D A]]
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[[Category: Large Structures]]
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[[Category: Li, S H]]
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[[Category: Lawrence DA]]
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[[Category: Stuckey, J A]]
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[[Category: Li S-H]]
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[[Category: Blood clotting]]
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[[Category: Stuckey JA]]
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[[Category: Blood clotting-inhibitor complex]]
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[[Category: Inhibitor]]
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[[Category: Pai-1]]
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[[Category: Serpin]]
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Current revision

Crystal Structure of a novel small molecule inactivator bound to plasminogen activator inhibitor-1

PDB ID 4g8r

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