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| | <StructureSection load='5za9' size='340' side='right'caption='[[5za9]], [[Resolution|resolution]] 1.62Å' scene=''> | | <StructureSection load='5za9' size='340' side='right'caption='[[5za9]], [[Resolution|resolution]] 1.62Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5za9]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZA9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5ZA9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5za9]] is a 1 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=5ZA9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZA9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=50I:3-azanyl-5-(azepan-1-yl)-6-(1-benzofuran-2-yl)-Ncarbamimidoyl-pyrazine-2-carboxamide'>50I</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]] 1.62Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/U-plasminogen_activator U-plasminogen activator], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.73 3.4.21.73] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=50I:3-azanyl-5-(azepan-1-yl)-6-(1-benzofuran-2-yl)-Ncarbamimidoyl-pyrazine-2-carboxamide'>50I</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5za9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5za9 OCA], [http://pdbe.org/5za9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5za9 RCSB], [http://www.ebi.ac.uk/pdbsum/5za9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5za9 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=5za9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5za9 OCA], [https://pdbe.org/5za9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5za9 RCSB], [https://www.ebi.ac.uk/pdbsum/5za9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5za9 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/UROK_HUMAN UROK_HUMAN]] Defects in PLAU are the cause of Quebec platelet disorder (QPD) [MIM:[http://omim.org/entry/601709 601709]]. QPD is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins.<ref>PMID:20007542</ref> | + | [https://www.uniprot.org/uniprot/UROK_HUMAN UROK_HUMAN] Defects in PLAU are the cause of Quebec platelet disorder (QPD) [MIM:[https://omim.org/entry/601709 601709]. QPD is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins.<ref>PMID:20007542</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UROK_HUMAN UROK_HUMAN]] Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. | + | [https://www.uniprot.org/uniprot/UROK_HUMAN UROK_HUMAN] Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. |
| | <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 5za9" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5za9" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Urokinase 3D Structures|Urokinase 3D Structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: U-plasminogen activator]]
| + | [[Category: Buckley BJ]] |
| - | [[Category: Buckley, B J]] | + | [[Category: Huang MD]] |
| - | [[Category: Huang, M D]] | + | [[Category: Jiang LG]] |
| - | [[Category: Jiang, L G]] | + | [[Category: Kelso MJ]] |
| - | [[Category: Kelso, M J]] | + | [[Category: Ranson M]] |
| - | [[Category: Ranson, M]] | + | |
| - | [[Category: Amiloride]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Urokinase]]
| + | |
| Structural highlights
Disease
UROK_HUMAN Defects in PLAU are the cause of Quebec platelet disorder (QPD) [MIM:601709. QPD is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins.[1]
Function
UROK_HUMAN Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.
Publication Abstract from PubMed
Metastasis is the cause of death in the majority ( approximately 90%) of malignant cancers. The oral potassium-sparing diuretic amiloride and its 5-substituted derivative 5 -N, N-(hexamethylene)amiloride (HMA) reportedly show robust antitumor/metastasis effects in multiple in vitro and animal models. These effects are likely due, at least in part, to inhibition of the urokinase plasminogen activator (uPA), a key protease determinant of cell invasiveness and metastasis. This study reports the discovery of 6-substituted HMA analogs that show nanomolar potency against uPA, high selectivity over related trypsin-like serine proteases, and minimal inhibitory effects against epithelial sodium channels (ENaC), the diuretic and antikaliuretic target of amiloride. Reductions in lung metastases were demonstrated for two analogs in a late-stage experimental mouse metastasis model, and one analog completely inhibited formation of liver metastases in an orthotopic xenograft mouse model of pancreatic cancer. The results support further evaluation of 6-substituted HMA derivatives as uPA-targeting anticancer drugs.
6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer.,Buckley BJ, Aboelela A, Minaei E, Jiang LX, Xu Z, Ali U, Fildes K, Cheung CY, Cook SM, Johnson DC, Bachovchin DA, Cook GM, Apte M, Huang M, Ranson M, Kelso MJ J Med Chem. 2018 Sep 27;61(18):8299-8320. doi: 10.1021/acs.jmedchem.8b00838. Epub, 2018 Sep 7. PMID:30130401[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Paterson AD, Rommens JM, Bharaj B, Blavignac J, Wong I, Diamandis M, Waye JS, Rivard GE, Hayward CP. Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene. Blood. 2010 Feb 11;115(6):1264-6. doi: 10.1182/blood-2009-07-233965. Epub 2009, Dec 9. PMID:20007542 doi:10.1182/blood-2009-07-233965
- ↑ Buckley BJ, Aboelela A, Minaei E, Jiang LX, Xu Z, Ali U, Fildes K, Cheung CY, Cook SM, Johnson DC, Bachovchin DA, Cook GM, Apte M, Huang M, Ranson M, Kelso MJ. 6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer. J Med Chem. 2018 Sep 27;61(18):8299-8320. doi: 10.1021/acs.jmedchem.8b00838. Epub, 2018 Sep 7. PMID:30130401 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00838
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