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| | ==Michaelis complex of tPA-S195A:PAI-1== | | ==Michaelis complex of tPA-S195A:PAI-1== |
| - | <StructureSection load='5brr' size='340' side='right' caption='[[5brr]], [[Resolution|resolution]] 3.16Å' scene=''> | + | <StructureSection load='5brr' size='340' side='right'caption='[[5brr]], [[Resolution|resolution]] 3.16Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5brr]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BRR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BRR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5brr]] 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=5BRR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BRR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></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]] 3.16Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/T-plasminogen_activator T-plasminogen activator], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.68 3.4.21.68] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></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=5brr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5brr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5brr RCSB], [http://www.ebi.ac.uk/pdbsum/5brr PDBsum]</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=5brr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5brr OCA], [https://pdbe.org/5brr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5brr RCSB], [https://www.ebi.ac.uk/pdbsum/5brr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5brr 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. [[http://www.uniprot.org/uniprot/TPA_HUMAN TPA_HUMAN]] Note=Increased activity of TPA results in increased fibrinolysis of fibrin blood clots that is associated with excessive bleeding. Defective release of TPA results in hypofibrinolysis that can lead to thrombosis or embolism. | + | [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> [[http://www.uniprot.org/uniprot/TPA_HUMAN TPA_HUMAN]] Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation, in cell migration and many other physiopathological events. Plays a direct role in facilitating neuronal migration. | + | [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 == |
| | + | Thrombosis is a leading cause of death worldwide. Recombinant tissue-type plasminogen activator (tPA) is the FDA-approved thrombolytic drug. tPA is rapidly inactivated by endogenous plasminogen activators inhibitor-1 (PAI-1). Engineering on tPA to reduce its inhibition by PAI-1 without compromising its thrombolytic effect is a continuous effort. Precise details, with atomic resolution, of the molecular interactions between tPA and PAI-1 remains unknown despite extensive previous studies. Here, we report the crystal structure of tPA.PAI-1 Michaelis complex, which shows significant differences from the structure of its urokinase-type plasminogen activator (uPA) analogue, the uPA.PAI-1 Michaelis complex. The PAI-1 reactive center loop (RCL) adopts a unique kinked conformation, and the first 5 residues of RCL bends toward the beta-sheet A. The structure provides detailed interactions between tPA 37- and 60-loops with PAI-1. On the tPA side, the S2 and S1beta pockets opens up to accommodate PAI-1. This study lays down a foundation for understanding the specificity of PAI-1 for tPA, and provides structural clues to design newer generation of thrombolytic agents with reduced PAI-1 inactivation. |
| | + | |
| | + | Crystal Structure of the Michaelis Complex between Tissue-type Plasminogen Activator and Plasminogen Activators Inhibitor-1.,Gong L, Liu M, Zeng T, Shi X, Yuan C, Andreasen PA, Huang M J Biol Chem. 2015 Aug 31. pii: jbc.M115.677567. PMID:26324706<ref>PMID:26324706</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 5brr" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Plasminogen activator|Plasminogen activator]] |
| | + | *[[Plasminogen activator inhibitor|Plasminogen activator inhibitor]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: T-plasminogen activator]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Gong, L]] | + | [[Category: Large Structures]] |
| - | [[Category: Hydrolase inhibitor-hydrolase complex]] | + | [[Category: Gong L]] |
| - | [[Category: Plasminogen activator inhibitor 1]]
| + | |
| - | [[Category: Structure-activity relationship]]
| + | |
| - | [[Category: Thrombolysis]]
| + | |
| - | [[Category: Tissue-type plasminogen activator catalytic domain]]
| + | |
| 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
Thrombosis is a leading cause of death worldwide. Recombinant tissue-type plasminogen activator (tPA) is the FDA-approved thrombolytic drug. tPA is rapidly inactivated by endogenous plasminogen activators inhibitor-1 (PAI-1). Engineering on tPA to reduce its inhibition by PAI-1 without compromising its thrombolytic effect is a continuous effort. Precise details, with atomic resolution, of the molecular interactions between tPA and PAI-1 remains unknown despite extensive previous studies. Here, we report the crystal structure of tPA.PAI-1 Michaelis complex, which shows significant differences from the structure of its urokinase-type plasminogen activator (uPA) analogue, the uPA.PAI-1 Michaelis complex. The PAI-1 reactive center loop (RCL) adopts a unique kinked conformation, and the first 5 residues of RCL bends toward the beta-sheet A. The structure provides detailed interactions between tPA 37- and 60-loops with PAI-1. On the tPA side, the S2 and S1beta pockets opens up to accommodate PAI-1. This study lays down a foundation for understanding the specificity of PAI-1 for tPA, and provides structural clues to design newer generation of thrombolytic agents with reduced PAI-1 inactivation.
Crystal Structure of the Michaelis Complex between Tissue-type Plasminogen Activator and Plasminogen Activators Inhibitor-1.,Gong L, Liu M, Zeng T, Shi X, Yuan C, Andreasen PA, Huang M J Biol Chem. 2015 Aug 31. pii: jbc.M115.677567. PMID:26324706[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
- ↑ Gong L, Liu M, Zeng T, Shi X, Yuan C, Andreasen PA, Huang M. Crystal Structure of the Michaelis Complex between Tissue-type Plasminogen Activator and Plasminogen Activators Inhibitor-1. J Biol Chem. 2015 Aug 31. pii: jbc.M115.677567. PMID:26324706 doi:http://dx.doi.org/10.1074/jbc.M115.677567
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