View source for 4cik


==plasminogen kringle 1 in complex with inhibitor==
<StructureSection load='4cik' size='340' side='right'caption='[[4cik]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4cik]] 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=4CIK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CIK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.78&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XO3:5-[(2R,4S)-2-(PHENYLMETHYL)PIPERIDIN-4-YL]-1,2-OXAZOL-3-ONE'>XO3</scene></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=4cik FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cik OCA], [https://pdbe.org/4cik PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cik RCSB], [https://www.ebi.ac.uk/pdbsum/4cik PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cik ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PLMN_HUMAN PLMN_HUMAN] Defects in PLG are the cause of plasminogen deficiency (PLGD) [MIM:[https://omim.org/entry/217090 217090]. PLGD is characterized by decreased serum plasminogen activity. Two forms of the disorder are distinguished: type 1 deficiency is additionally characterized by decreased plasminogen antigen levels and clinical symptoms, whereas type 2 deficiency, also known as dysplasminogenemia, is characterized by normal, or slightly reduced antigen levels, and absence of clinical manifestations. Plasminogen deficiency type 1 results in markedly impaired extracellular fibrinolysis and chronic mucosal pseudomembranous lesions due to subepithelial fibrin deposition and inflammation. The most common clinical manifestation of type 1 deficiency is ligneous conjunctivitis in which pseudomembranes formation on the palpebral surfaces of the eye progresses to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa.<ref>PMID:1986355</ref> <ref>PMID:8392398</ref> <ref>PMID:6216475</ref> <ref>PMID:6238949</ref> <ref>PMID:1427790</ref> <ref>PMID:9242524</ref> <ref>PMID:9858247</ref> <ref>PMID:10233898</ref> 
== Function ==
[https://www.uniprot.org/uniprot/PLMN_HUMAN PLMN_HUMAN] Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells.<ref>PMID:14699093</ref>   Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo.<ref>PMID:14699093</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein-protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.44 muM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.

Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a Protein-Protein Interaction.,Cheng L, Pettersen D, Ohlsson B, Schell P, Karle M, Evertsson E, Pahlen S, Jonforsen M, Plowright AT, Bostrom J, Fex T, Thelin A, Hilgendorf C, Xue Y, Wahlund G, Lindberg W, Larsson LO, Gustafsson D ACS Med Chem Lett. 2014 Feb 18;5(5):538-43. doi: 10.1021/ml400526d. eCollection, 2014 May 8. PMID:24900876<ref>PMID:24900876</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4cik" style="background-color:#fffaf0;"></div>

==See Also==
*[[Plasminogen 3D structures|Plasminogen 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cheng L]]
[[Category: Gustafsson D]]
[[Category: Johansson C]]
[[Category: Pettersen D]]
[[Category: Xue Y]]