4ish

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{{STRUCTURE_4ish| PDB=4ish | SCENE= }}
 
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===Structure of FACTOR VIIA in complex with the inhibitor BMS-593214 also known as 2'-[(6R,6AR,11BR)-2-CARBAMIMIDOYL-6,6A,7,11B-TETRAHYDRO-5H-INDENO[2,1-C]QUINOLIN-6-YL]-5'-HYDROXY-4'-METHOXYBIPHENYL-4-CARBOXYLIC ACID===
 
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{{ABSTRACT_PUBMED_23478148}}
 
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==Disease==
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==Structure of FACTOR VIIA in complex with the inhibitor BMS-593214 also known as 2'-[(6R,6AR,11BR)-2-CARBAMIMIDOYL-6,6A,7,11B-TETRAHYDRO-5H-INDENO[2,1-C]QUINOLIN-6-YL]-5'-HYDROXY-4'-METHOXYBIPHENYL-4-CARBOXYLIC ACID==
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[[http://www.uniprot.org/uniprot/FA7_HUMAN FA7_HUMAN]] Defects in F7 are the cause of factor VII deficiency (FA7D) [MIM:[http://omim.org/entry/227500 227500]]. A hemorrhagic disease with variable presentation. The clinical picture can be very severe, with the early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, moderate with cutaneous-mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by a surgical intervention. Finally, numerous subjects are completely asymptomatic despite very low factor VII levels.<ref>PMID:8043443</ref> <ref>PMID:2070047</ref> <ref>PMID:1634227</ref> <ref>PMID:8364544</ref> <ref>PMID:8204879</ref> <ref>PMID:7981691</ref> <ref>PMID:7974346</ref> <ref>PMID:8652821</ref> <ref>PMID:8844208</ref> <ref>PMID:8940045</ref> <ref>PMID:8883260</ref> <ref>PMID:9414278</ref> <ref>PMID:9576180</ref> <ref>PMID:9452082</ref> <ref>PMID:11091194</ref> <ref>PMID:11129332</ref> <ref>PMID:10862079</ref> <ref>PMID:12472587</ref> <ref>PMID:14717781</ref> <ref>PMID:19751712</ref> <ref>PMID:18976247</ref> <ref>PMID:19432927</ref> <ref>PMID:21206266</ref> <ref>PMID:21372693</ref>
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<StructureSection load='4ish' size='340' side='right'caption='[[4ish]], [[Resolution|resolution]] 1.82&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4ish]] 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=4ISH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ISH FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.82&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1GE:2-[(6R,6AR,11BR)-2-CARBAMIMIDOYL-6,6A,7,11B-TETRAHYDRO-5H-INDENO[2,1-C]QUINOLIN-6-YL]-5-HYDROXY-4-METHOXYBIPHENYL-4-CARBOXYLIC+ACID'>1GE</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ish FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ish OCA], [https://pdbe.org/4ish PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ish RCSB], [https://www.ebi.ac.uk/pdbsum/4ish PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ish ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/FA7_HUMAN FA7_HUMAN] Defects in F7 are the cause of factor VII deficiency (FA7D) [MIM:[https://omim.org/entry/227500 227500]. A hemorrhagic disease with variable presentation. The clinical picture can be very severe, with the early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, moderate with cutaneous-mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by a surgical intervention. Finally, numerous subjects are completely asymptomatic despite very low factor VII levels.<ref>PMID:8043443</ref> <ref>PMID:2070047</ref> <ref>PMID:1634227</ref> <ref>PMID:8364544</ref> <ref>PMID:8204879</ref> <ref>PMID:7981691</ref> <ref>PMID:7974346</ref> <ref>PMID:8652821</ref> <ref>PMID:8844208</ref> <ref>PMID:8940045</ref> <ref>PMID:8883260</ref> <ref>PMID:9414278</ref> <ref>PMID:9576180</ref> <ref>PMID:9452082</ref> <ref>PMID:11091194</ref> <ref>PMID:11129332</ref> <ref>PMID:10862079</ref> <ref>PMID:12472587</ref> <ref>PMID:14717781</ref> <ref>PMID:19751712</ref> <ref>PMID:18976247</ref> <ref>PMID:19432927</ref> <ref>PMID:21206266</ref> <ref>PMID:21372693</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/FA7_HUMAN FA7_HUMAN] Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. Factor VIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A 6-amidinotetrahydroquinoline screening hit was driven to a structurally novel, potent, and selective FVIIa inhibitor through a combination of library synthesis and rational design. An efficient gram-scale synthesis of the active enantiomer BMS-593214 was developed, which required significant optimization of the key Povarov annulation. Importantly, BMS-593214 showed antithrombotic efficacy in a rabbit arterial thrombosis model. A crystal structure of BMS-593214 bound to FVIIa highlights key contacts with Asp 189, Lys 192, and the S2 pocket.
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==Function==
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Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor.,Priestley ES, De Lucca I, Zhou J, Zhou J, Saiah E, Stanton R, Robinson L, Luettgen JM, Wei A, Wen X, Knabb RM, Wong PC, Wexler RR Bioorg Med Chem Lett. 2013 Feb 14. pii: S0960-894X(13)00187-X. doi:, 10.1016/j.bmcl.2013.02.013. PMID:23478148<ref>PMID:23478148</ref>
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[[http://www.uniprot.org/uniprot/FA7_HUMAN FA7_HUMAN]] Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. Factor VIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4ish]] 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=4ISH OCA].
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</div>
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<div class="pdbe-citations 4ish" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<references group="xtra"/><references/>
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*[[Factor VIIa 3D structures|Factor VIIa 3D structures]]
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[[Category: Coagulation factor VIIa]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Wei, A.]]
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[[Category: Large Structures]]
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[[Category: Blood coagulation factor]]
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[[Category: Wei A]]
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[[Category: Calcium-binding]]
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[[Category: Glycoprotein]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Plasma]]
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[[Category: Protein inhibitor complex]]
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[[Category: Serine protease]]
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Current revision

Structure of FACTOR VIIA in complex with the inhibitor BMS-593214 also known as 2'-[(6R,6AR,11BR)-2-CARBAMIMIDOYL-6,6A,7,11B-TETRAHYDRO-5H-INDENO[2,1-C]QUINOLIN-6-YL]-5'-HYDROXY-4'-METHOXYBIPHENYL-4-CARBOXYLIC ACID

PDB ID 4ish

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