View source for 5l30


==Factor VIIa in complex with the inhibitor (2R,15R)-2-[(1-aminoisoquinolin-6-yl)amino]-4,15,17-trimethyl-7-[1-(1H-tetrazol-5-yl)cyclopropyl]-13-oxa-4,11-diazatricyclo[14.2.2.1~6,10~]henicosa-1(18),6(21),7,9,16,19-hexaene-3,12-dione==
<StructureSection load='5l30' size='340' side='right'caption='[[5l30]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5l30]] 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=5L30 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5L30 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=70A:(2R,15R)-2-[(1-AMINOISOQUINOLIN-6-YL)AMINO]-4,15,17-TRIMETHYL-7-[1-(1H-TETRAZOL-5-YL)CYCLOPROPYL]-13-OXA-4,11-DIAZATRICYCLO[14.2.2.1~6,10~]HENICOSA-1(18),6(21),7,9,16,19-HEXAENE-3,12-DIONE'>70A</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">F7 ([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/Coagulation_factor_VIIa Coagulation factor VIIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.21 3.4.21.21] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5l30 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l30 OCA], [http://pdbe.org/5l30 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l30 RCSB], [http://www.ebi.ac.uk/pdbsum/5l30 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l30 ProSAT]</span></td></tr>
</table>
== Disease ==
[[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>  
== Function ==
[[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. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.

Synthesis and P1' SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors.,Ladziata VU, Glunz PW, Zou Y, Zhang X, Jiang W, Jacutin-Porte S, Cheney DL, Wei A, Luettgen JM, Harper TM, Wong PC, Seiffert D, Wexler RR, Priestley ES Bioorg Med Chem Lett. 2016 Aug 28. pii: S0960-894X(16)30920-9. doi:, 10.1016/j.bmcl.2016.08.088. PMID:27612545<ref>PMID:27612545</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5l30" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Coagulation factor VIIa]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Wei, A]]
[[Category: Blood coagulation factor]]
[[Category: Calcium-binding]]
[[Category: Glycoprotein]]
[[Category: Hydrolase]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Plasma]]
[[Category: Protein inhibitor complex]]
[[Category: Serine protease]]