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| | ==The crystal structure of uPA complex with peptide inhibitor MH027 at pH7.4== | | ==The crystal structure of uPA complex with peptide inhibitor MH027 at pH7.4== |
| - | <StructureSection load='3oy5' size='340' side='right' caption='[[3oy5]], [[Resolution|resolution]] 2.31Å' scene=''> | + | <StructureSection load='3oy5' size='340' side='right'caption='[[3oy5]], [[Resolution|resolution]] 2.31Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3oy5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OY5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OY5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3oy5]] 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=3OY5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OY5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.31Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2nwn|2nwn]], [[3ox7|3ox7]], [[3oy6|3oy6]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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 Homo sapiens])</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=3oy5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oy5 OCA], [https://pdbe.org/3oy5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3oy5 RCSB], [https://www.ebi.ac.uk/pdbsum/3oy5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3oy5 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>
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| - | <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=3oy5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oy5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3oy5 RCSB], [http://www.ebi.ac.uk/pdbsum/3oy5 PDBsum]</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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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 3oy5" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Urokinase|Urokinase]] | + | *[[Urokinase 3D Structures|Urokinase 3D Structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: U-plasminogen activator]] | + | [[Category: Large Structures]] |
| - | [[Category: Andreasen, P A]] | + | [[Category: Andreasen PA]] |
| - | [[Category: Huang, M D]] | + | [[Category: Huang MD]] |
| - | [[Category: Jiang, L G]] | + | [[Category: Jiang LG]] |
| - | [[Category: Hydrolase]]
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| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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| - | [[Category: Peptidyl inhibitor]]
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| - | [[Category: Pharmacophore]]
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| - | [[Category: Urokinase-type plasminogen activator]]
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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
Serine proteases are classical objects for studies of catalytic and inhibitory mechanisms as well as interesting as therapeutic targets. Since small-molecule serine protease inhibitors generally suffer from specificity problems, peptidic inhibitors, isolated from phage-displayed peptide libraries, have attracted considerable attention. Here, we have investigated the mechanism of binding of peptidic inhibitors to serine protease targets. Our model is upain-1 (CSWRGLENHRMC), a disulfide-bond-constrained competitive inhibitor of human urokinase-type plasminogen activator with a noncanonical inhibitory mechanism and an unusually high specificity. Using a number of modified variants of upain-1, we characterised the upain-1-urokinase-type plasminogen activator complex using X-ray crystal structure analysis, determined a model of the peptide in solution by NMR spectroscopy, and analysed binding kinetics and thermodynamics by surface plasmon resonance and isothermal titration calorimetry. We found that upain-1 changes both main-chain conformation and side-chain orientations as it binds to the protease, in particular its Trp3 residue and the surrounding backbone. The properties of upain-1 are strongly influenced by the addition of three to four amino acids long N-terminal and C-terminal extensions to the core, disulfide-bond-constrained sequence: The C-terminal extension stabilises the solution structure compared to the core peptide alone, and the protease-bound structure of the peptide is stabilised by intrapeptide contacts between the N-terminal extension and the core peptide around Trp3. These results provide a uniquely detailed description of the binding of a peptidic protease inhibitor to its target and are of general importance in the development of peptidic inhibitors with high specificity and new inhibitory mechanisms.
The binding mechanism of a peptidic cyclic serine protease inhibitor.,Jiang L, Svane AS, Sorensen HP, Jensen JK, Hosseini M, Chen Z, Weydert C, Nielsen JT, Christensen A, Yuan C, Jensen KJ, Nielsen NC, Malmendal A, Huang M, Andreasen PA J Mol Biol. 2011 Sep 16;412(2):235-50. Epub 2011 Jul 23. PMID:21802428[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
- ↑ Jiang L, Svane AS, Sorensen HP, Jensen JK, Hosseini M, Chen Z, Weydert C, Nielsen JT, Christensen A, Yuan C, Jensen KJ, Nielsen NC, Malmendal A, Huang M, Andreasen PA. The binding mechanism of a peptidic cyclic serine protease inhibitor. J Mol Biol. 2011 Sep 16;412(2):235-50. Epub 2011 Jul 23. PMID:21802428 doi:10.1016/j.jmb.2011.07.028
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