View source for 4isi


==Structure of FACTOR VIIA in complex with the inhibitor (6S)-N-(4-CARBAMIMIDOYLBENZYL)-1-CHLORO-3-(CYCLOBUTYLAMINO)-8,8-DIETHYL-4-OXO-4,6,7,8-TETRAHYDROPYRROLO[1,2-A]PYRAZINE-6-CARBOXAMIDE==
<StructureSection load='4isi' size='340' side='right'caption='[[4isi]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4isi]] 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=4ISI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ISI 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]] 1.94&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1GG:(6S)-N-(4-CARBAMIMIDOYLBENZYL)-1-CHLORO-3-(CYCLOBUTYLAMINO)-8,8-DIETHYL-4-OXO-4,6,7,8-TETRAHYDROPYRROLO[1,2-A]PYRAZINE-6-CARBOXAMIDE'>1GG</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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=4isi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4isi OCA], [https://pdbe.org/4isi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4isi RCSB], [https://www.ebi.ac.uk/pdbsum/4isi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4isi ProSAT]</span></td></tr>
</table>
== Disease ==
[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> 
== Function ==
[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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== Publication Abstract from PubMed ==
Bicyclic pyrazinone and pyrimidinone amides were designed and synthesized as potent TF-FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity.

Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors.,Zhang X, Glunz PW, Jiang W, Schmitt A, Newman M, Barbera FA, Bozarth JM, Rendina AR, Wei A, Wen X, Rossi KA, Luettgen JM, Wong PC, Knabb RM, Wexler RR, Scott Priestley E Bioorg Med Chem Lett. 2013 Mar 15;23(6):1604-7. doi: 10.1016/j.bmcl.2013.01.094. , Epub 2013 Jan 30. PMID:23416003<ref>PMID:23416003</ref>

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

==See Also==
*[[Factor VIIa 3D structures|Factor VIIa 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Wei A]]