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[[Image:2vio.jpg|left|200px]]
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{{STRUCTURE_2vio|  PDB=2vio  |  SCENE=  }}
'''FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR'''


==Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator==
<StructureSection load='2vio' size='340' side='right'caption='[[2vio]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2vio]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VIO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VIO FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=L1O:4-(2-AMINOETHOXY)-3,5-DICHLOROBENZOIC+ACID'>L1O</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1c5x|1c5x]], [[1gj9|1gj9]], [[1w0z|1w0z]], [[1fv9|1fv9]], [[1vja|1vja]], [[1gj8|1gj8]], [[1w11|1w11]], [[1sqo|1sqo]], [[1gjd|1gjd]], [[1w10|1w10]], [[1owk|1owk]], [[1w12|1w12]], [[1gi9|1gi9]], [[1o5a|1o5a]], [[1c5z|1c5z]], [[1owj|1owj]], [[1gi7|1gi7]], [[1o5b|1o5b]], [[1gjc|1gjc]], [[1sc8|1sc8]], [[1gja|1gja]], [[1o3p|1o3p]], [[1owe|1owe]], [[1sqa|1sqa]], [[1gjb|1gjb]], [[1f92|1f92]], [[1owi|1owi]], [[1kdu|1kdu]], [[1sqt|1sqt]], [[1f5l|1f5l]], [[1owd|1owd]], [[1ejn|1ejn]], [[1lmw|1lmw]], [[1u6q|1u6q]], [[1gi8|1gi8]], [[2jde|2jde]], [[1c5y|1c5y]], [[1w14|1w14]], [[1vj9|1vj9]], [[1w13|1w13]], [[1gj7|1gj7]], [[1c5w|1c5w]], [[1owh|1owh]], [[1o5c|1o5c]], [[2vin|2vin]], [[2vip|2vip]], [[2viq|2viq]], [[2viv|2viv]], [[2viw|2viw]]</div></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/U-plasminogen_activator U-plasminogen activator], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=2vio FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vio OCA], [https://pdbe.org/2vio PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vio RCSB], [https://www.ebi.ac.uk/pdbsum/2vio PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vio ProSAT]</span></td></tr>
</table>
== Disease ==
[[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 ==
[[https://www.uniprot.org/uniprot/UROK_HUMAN UROK_HUMAN]] Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vi/2vio_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2vio ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Fragment-based lead discovery has been applied to urokinase-type plasminogen activator (uPA). The (R)-enantiomer of the orally active drug mexiletine 5 (a fragment hit from X-ray crystallographic screening) was the chemical starting point. Structure-aided design led to elaborated inhibitors that retained the key interactions of (R)-5 while gaining extra potency by simultaneously occupying neighboring regions of the active site. Subsequent optimization led to 15, a potent, selective, and orally bioavailable inhibitor of uPA.


==Overview==
Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator.,Frederickson M, Callaghan O, Chessari G, Congreve M, Cowan SR, Matthews JE, McMenamin R, Smith DM, Vinkovic M, Wallis NG J Med Chem. 2008 Jan 24;51(2):183-6. Epub 2007 Dec 29. PMID:18163548<ref>PMID:18163548</ref>
Fragment-based lead discovery has been applied to urokinase-type plasminogen activator (uPA). The (R)-enantiomer of the orally active drug mexiletine 5 (a fragment hit from X-ray crystallographic screening) was the chemical starting point. Structure-aided design led to elaborated inhibitors that retained the key interactions of (R)-5 while gaining extra potency by simultaneously occupying neighboring regions of the active site. Subsequent optimization led to 15, a potent, selective, and orally bioavailable inhibitor of uPA.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2VIO is a [[Single protein]] structure of 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=2VIO OCA].
</div>
<div class="pdbe-citations 2vio" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator., Frederickson M, Callaghan O, Chessari G, Congreve M, Cowan SR, Matthews JE, McMenamin R, Smith DM, Vinkovic M, Wallis NG, J Med Chem. 2008 Jan 24;51(2):183-6. Epub 2007 Dec 29. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18163548 18163548]
*[[Urokinase 3D Structures|Urokinase 3D Structures]]
[[Category: Homo sapiens]]
== References ==
[[Category: Single protein]]
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: U-plasminogen activator]]
[[Category: U-plasminogen activator]]
[[Category: Callaghan, O.]]
[[Category: Callaghan, O]]
[[Category: Chessari, G.]]
[[Category: Chessari, G]]
[[Category: Congreve, M.]]
[[Category: Congreve, M]]
[[Category: Cowan, S R.]]
[[Category: Cowan, S R]]
[[Category: Frederickson, M.]]
[[Category: Frederickson, M]]
[[Category: Matthews, J E.]]
[[Category: Matthews, J E]]
[[Category: Mcmenamin, R.]]
[[Category: McMenamin, R]]
[[Category: Smith, D.]]
[[Category: Smith, D]]
[[Category: Vinkovic, M.]]
[[Category: Vinkovic, M]]
[[Category: Wallis, N G.]]
[[Category: Wallis, N G]]
[[Category: Blood coagulation]]
[[Category: Blood coagulation]]
[[Category: Egf-like domain]]
[[Category: Egf-like domain]]
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[[Category: Urokinase-type plasminogen activator]]
[[Category: Urokinase-type plasminogen activator]]
[[Category: Zymogen]]
[[Category: Zymogen]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 18:52:52 2008''
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