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| | ==Potent and selective bicyclic peptide inhibitor (UK18) of human urokinase-type plasminogen activator(uPA)== | | ==Potent and selective bicyclic peptide inhibitor (UK18) of human urokinase-type plasminogen activator(uPA)== |
| - | <StructureSection load='3qn7' size='340' side='right' caption='[[3qn7]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='3qn7' size='340' side='right'caption='[[3qn7]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3qn7]] 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=3QN7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QN7 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3qn7]] 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=3QN7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QN7 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZBR:1,3,5-TRIS(BROMOMETHYL)BENZENE'>ZBR</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]] 1.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1lmw|1lmw]], [[2nwn|2nwn]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZBR:1,3,5-TRIS(BROMOMETHYL)BENZENE'>ZBR</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PLAU ([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'>[https://proteopedia.org/fgij/fg.htm?mol=3qn7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qn7 OCA], [https://pdbe.org/3qn7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qn7 RCSB], [https://www.ebi.ac.uk/pdbsum/3qn7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qn7 ProSAT]</span></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='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=3qn7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qn7 OCA], [http://pdbe.org/3qn7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3qn7 RCSB], [http://www.ebi.ac.uk/pdbsum/3qn7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3qn7 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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| | ==See Also== | | ==See Also== |
| - | *[[Urokinase|Urokinase]] | + | *[[Urokinase 3D Structures|Urokinase 3D Structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: U-plasminogen activator]] | + | [[Category: Large Structures]] |
| - | [[Category: Angelini, A]] | + | [[Category: Angelini A]] |
| - | [[Category: Cendron, L]] | + | [[Category: Cendron L]] |
| - | [[Category: Heinis, C]] | + | [[Category: Heinis C]] |
| - | [[Category: Touati, J]] | + | [[Category: Touati J]] |
| - | [[Category: Winter, G]] | + | [[Category: Winter G]] |
| - | [[Category: Zanotti, G]] | + | [[Category: Zanotti G]] |
| - | [[Category: Bicyclic peptide inhibitor]]
| + | |
| - | [[Category: Chymotrypsin fold]]
| + | |
| - | [[Category: Extracellular]]
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| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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| - | [[Category: Serine protease]]
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| 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
From a large combinatorial library of chemically constrained bicyclic peptides we isolated a selective and potent (K(i) = 53 nM) inhibitor of human urokinase-type plasminogen activator (uPA) and crystallized the complex. This revealed an extended structure of the peptide with both peptide loops engaging the target to form a large interaction surface of 701 A(2) with multiple hydrogen bonds and complementary charge interactions, explaining the high affinity and specificity of the inhibitor. The interface resembles that between two proteins and suggests that these constrained peptides have the potential to act as small protein mimics.
Bicyclic peptide inhibitor reveals large contact interface with a protease target.,Angelini A, Cendron L, Chen S, Touati J, Winter G, Zanotti G, Heinis C ACS Chem Biol. 2012 May 18;7(5):817-21. doi: 10.1021/cb200478t. Epub 2012 Feb 15. PMID:22304751[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
- ↑ Angelini A, Cendron L, Chen S, Touati J, Winter G, Zanotti G, Heinis C. Bicyclic peptide inhibitor reveals large contact interface with a protease target. ACS Chem Biol. 2012 May 18;7(5):817-21. doi: 10.1021/cb200478t. Epub 2012 Feb 15. PMID:22304751 doi:http://dx.doi.org/10.1021/cb200478t
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