|
|
| Line 1: |
Line 1: |
| | | | |
| | ==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== |
| - | <StructureSection load='4g8o' size='340' side='right' caption='[[4g8o]], [[Resolution|resolution]] 2.71Å' scene=''> | + | <StructureSection load='4g8o' size='340' side='right'caption='[[4g8o]], [[Resolution|resolution]] 2.71Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4g8o]] is a 4 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=4G8O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G8O FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4g8o]] is a 4 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=4G8O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G8O FirstGlance]. <br> |
| - | </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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1b3k|1b3k]], [[4g8r|4g8r]]</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=4g8o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g8o OCA], [https://pdbe.org/4g8o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g8o RCSB], [https://www.ebi.ac.uk/pdbsum/4g8o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g8o ProSAT]</span></td></tr> |
| - | <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>
| + | |
| - | <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=4g8o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g8o OCA], [http://pdbe.org/4g8o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4g8o RCSB], [http://www.ebi.ac.uk/pdbsum/4g8o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4g8o ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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. | + | [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 == |
| - | [[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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 22: |
Line 20: |
| | </div> | | </div> |
| | <div class="pdbe-citations 4g8o" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4g8o" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Plasminogen activator inhibitor|Plasminogen activator inhibitor]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Lawrence, D A]] | + | [[Category: Large Structures]] |
| - | [[Category: Li, S H]] | + | [[Category: Lawrence DA]] |
| - | [[Category: Stuckey, J A]] | + | [[Category: Li S-H]] |
| - | [[Category: Blood clotting]]
| + | [[Category: Stuckey JA]] |
| - | [[Category: Blood clotting-inhibitor complex]]
| + | |
| - | [[Category: Inhibitor]] | + | |
| - | [[Category: Pai-1]]
| + | |
| - | [[Category: Serpin]]
| + | |
| Structural highlights
Disease
PAI1_HUMAN Defects in SERPINE1 are the cause of plasminogen activator inhibitor-1 deficiency (PAI-1D) [MIM: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.[1] Note=High concentrations of SERPINE1 seem to contribute to the development of venous but not arterial occlusions.
Function
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.[2]
Publication Abstract from PubMed
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.
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Fay WP, Parker AC, Condrey LR, Shapiro AD. Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood. 1997 Jul 1;90(1):204-8. PMID:9207454
- ↑ Szabo R, Netzel-Arnett S, Hobson JP, Antalis TM, Bugge TH. Matriptase-3 is a novel phylogenetically preserved membrane-anchored serine protease with broad serpin reactivity. Biochem J. 2005 Aug 15;390(Pt 1):231-42. PMID:15853774 doi:BJ20050299
- ↑ Li SH, Reinke AA, Sanders KL, Emal CD, Whisstock JC, Stuckey JA, Lawrence DA. Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1. 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 doi:http://dx.doi.org/10.1073/pnas.1216499110
|
