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| | ==Discovery and characterisation of an antibody that selectively modulates the inhibitory activity of plasminogen activator inhibitor-1== | | ==Discovery and characterisation of an antibody that selectively modulates the inhibitory activity of plasminogen activator inhibitor-1== |
| - | <StructureSection load='6i8s' size='340' side='right' caption='[[6i8s]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='6i8s' size='340' side='right'caption='[[6i8s]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6i8s]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I8S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I8S FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6i8s]] is a 12 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=6I8S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6I8S FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SERPINE1, PAI1, PLANH1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</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=6i8s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i8s OCA], [http://pdbe.org/6i8s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6i8s RCSB], [http://www.ebi.ac.uk/pdbsum/6i8s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6i8s ProSAT]</span></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=6i8s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i8s OCA], [https://pdbe.org/6i8s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6i8s RCSB], [https://www.ebi.ac.uk/pdbsum/6i8s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6i8s 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 == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6i8s" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6i8s" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Antibody 3D structures|Antibody 3D structures]] |
| | + | *[[Plasminogen activator inhibitor|Plasminogen activator inhibitor]] |
| | + | *[[3D structures of non-human antibody|3D structures of non-human antibody]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacillus coli migula 1895]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Lundqvist, T]] | + | [[Category: Lundqvist T]] |
| - | [[Category: Popovic, B]] | + | [[Category: Popovic B]] |
| - | [[Category: Vousden, K A]] | + | [[Category: Vousden KA]] |
| - | [[Category: Antibody]]
| + | |
| - | [[Category: Blood clotting]]
| + | |
| - | [[Category: Fab]]
| + | |
| - | [[Category: Pai-1]]
| + | |
| - | [[Category: Plasminogen activator inhibitor-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-1 (PAI-1) is a serine protease inhibitor (serpin) that regulates fibrinolysis, cell adhesion and cell motility via its interactions with plasminogen activators and vitronectin. PAI-1 has been shown to play a role in a number of diverse pathologies including cardiovascular diseases, obesity and cancer and is therefore an attractive therapeutic target. However the multiple patho-physiological roles of PAI-1, and understanding the relative contributions of these in any one disease setting, make the development of therapeutically relevant molecules challenging. Here we describe the identification and characterisation of fully human antibody MEDI-579, which binds with high affinity and specificity to the active form of human PAI-1. MEDI-579 specifically inhibits serine protease interactions with PAI-1 while conserving vitronectin binding. Crystallographic analysis reveals that this specificity is achieved through direct binding of MEDI-579 Fab to the reactive centre loop (RCL) of PAI-1 and at the same exosite used by both tissue and urokinase plasminogen activators (tPA and uPA). We propose that MEDI-579 acts by directly competing with proteases for RCL binding and as such is able to modulate the interaction of PAI-1 with tPA and uPA in a way not previously described for a human PAI-1 inhibitor.
Discovery and characterisation of an antibody that selectively modulates the inhibitory activity of plasminogen activator inhibitor-1.,Vousden KA, Lundqvist T, Popovic B, Naiman B, Carruthers AM, Newton P, Johnson DJD, Pomowski A, Wilkinson T, Dufner P, de Mendez I, Mallinder PR, Murray C, Strain M, Connor J, Murray LA, Sleeman MA, Lowe DC, Huntington JA, Vaughan TJ Sci Rep. 2019 Feb 7;9(1):1605. doi: 10.1038/s41598-019-38842-x. PMID:30733557[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
- ↑ Vousden KA, Lundqvist T, Popovic B, Naiman B, Carruthers AM, Newton P, Johnson DJD, Pomowski A, Wilkinson T, Dufner P, de Mendez I, Mallinder PR, Murray C, Strain M, Connor J, Murray LA, Sleeman MA, Lowe DC, Huntington JA, Vaughan TJ. Discovery and characterisation of an antibody that selectively modulates the inhibitory activity of plasminogen activator inhibitor-1. Sci Rep. 2019 Feb 7;9(1):1605. doi: 10.1038/s41598-019-38842-x. PMID:30733557 doi:http://dx.doi.org/10.1038/s41598-019-38842-x
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