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| | ==The crystal structure of mupain-1-IG in complex with murinised human uPA at pH7.4== | | ==The crystal structure of mupain-1-IG in complex with murinised human uPA at pH7.4== |
| - | <StructureSection load='4zhl' size='340' side='right' caption='[[4zhl]], [[Resolution|resolution]] 2.06Å' scene=''> | + | <StructureSection load='4zhl' size='340' side='right'caption='[[4zhl]], [[Resolution|resolution]] 2.06Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4zhl]] 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=4ZHL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZHL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4zhl]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZHL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZHL FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zhm|4zhm]]</td></tr> | + | </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=4zhl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zhl OCA], [https://pdbe.org/4zhl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zhl RCSB], [https://www.ebi.ac.uk/pdbsum/4zhl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zhl ProSAT]</span></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='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=4zhl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zhl OCA], [http://pdbe.org/4zhl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zhl RCSB], [http://www.ebi.ac.uk/pdbsum/4zhl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zhl 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 4zhl" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4zhl" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Plasminogen activator|Plasminogen activator]] |
| | + | *[[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: Andreasen, P A]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Huang, M]] | + | [[Category: Andreasen PA]] |
| - | [[Category: Jiang, L]] | + | [[Category: Huang M]] |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]] | + | [[Category: Jiang L]] |
| - | [[Category: Peptides inhibitor]]
| + | |
| - | [[Category: Serine protease]]
| + | |
| - | [[Category: Upa]]
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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
We have developed a new concept for designing peptidic protein modulators, by recombinantly fusing the peptidic modulator, with randomized residues, directly to the target protein via a linker and screening for internal modulation of the activity of the protein. We tested the feasibility of the concept by fusing a 10-residue-long, disulfide-bond-constrained inhibitory peptide, randomized in selected positions, to the catalytic domain of the serine protease murine urokinase-type plasminogen activator. High-affinity inhibitory peptide variants were identified as those that conferred to the fusion protease the lowest activity for substrate hydrolysis. The usefulness of the strategy was demonstrated by the selection of peptidic inhibitors of murine urokinase-type plasminogen activator with a low nanomolar affinity. The high affinity could not have been predicted by rational considerations, as the high affinity was associated with a loss of polar interactions and an increased binding entropy.
Selection of High-Affinity Peptidic Serine Protease Inhibitors with Increased Binding Entropy from a Back-Flip Library of Peptide-Protease Fusions.,Sorensen HP, Xu P, Jiang L, Kromann-Hansen T, Jensen KJ, Huang M, Andreasen PA J Mol Biol. 2015 Sep 25;427(19):3110-22. doi: 10.1016/j.jmb.2015.08.005. Epub, 2015 Aug 14. PMID:26281711[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
- ↑ Sorensen HP, Xu P, Jiang L, Kromann-Hansen T, Jensen KJ, Huang M, Andreasen PA. Selection of High-Affinity Peptidic Serine Protease Inhibitors with Increased Binding Entropy from a Back-Flip Library of Peptide-Protease Fusions. J Mol Biol. 2015 Sep 25;427(19):3110-22. doi: 10.1016/j.jmb.2015.08.005. Epub, 2015 Aug 14. PMID:26281711 doi:http://dx.doi.org/10.1016/j.jmb.2015.08.005
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