1ygc: Difference between revisions

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-[[Image:1ygc.png|left|200px]]
-{{STRUCTURE_1ygc|  PDB=1ygc  |  SCENE=  }}
+==Short Factor VIIa with a small molecule inhibitor==
+<StructureSection load='1ygc' size='340' side='right'caption='[[1ygc]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1ygc]] 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=1YGC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1YGC 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]] 2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=905:(R)-4-[2-(3-AMINO-BENZENESULFONYLAMINO)-1-(3,5-DIETHOXY-2-FLUOROPHENYL)-2-OXO-ETHYLAMINO]-2-HYDROXY-BENZAMIDINE'>905</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1ygc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ygc OCA], [https://pdbe.org/1ygc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ygc RCSB], [https://www.ebi.ac.uk/pdbsum/1ygc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ygc 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.
+== 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/yg/1ygc_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=1ygc ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The serine protease factor VIIa (FVIIa) in complex with its cellular cofactor tissue factor (TF) initiates the blood coagulation reactions. TF.FVIIa is also implicated in thrombosis-related disorders and constitutes an appealing therapeutic target for treatment of cardiovascular diseases. To this end, we generated the FVIIa active site inhibitor G17905, which displayed great potency toward TF.FVIIa (Ki = 0.35 +/- 0.11 nM). G17905 did not appreciably inhibit 12 of the 14 examined trypsin-like serine proteases, consistent with its TF.FVIIa-specific activity in clotting assays. The crystal structure of the FVIIa.G17905 complex provides insight into the molecular basis of the high selectivity. It shows that, compared with other serine proteases, FVIIa is uniquely equipped to accommodate conformational disturbances in the Gln217-Gly219 region caused by the ortho-hydroxy group of the inhibitor's aminobenzamidine moiety located in the S1 recognition pocket. Moreover, the structure revealed a novel, nonstandard conformation of FVIIa active site in the region of the oxyanion hole, a "flipped" Lys192-Gly193 peptide bond. Macromolecular substrate activation assays demonstrated that G17905 is a noncompetitive, slow-binding inhibitor. Nevertheless, G17905 effectively inhibited thrombus formation in a baboon arterio-venous shunt model, reducing platelet and fibrin deposition by approximately 70% at 0.4 mg/kg + 0.1 mg/kg/min infusion. Therefore, the in vitro potency of G17905, characterized by slow binding kinetics, correlated with efficacious antithrombotic activity in vivo.
-===Short Factor VIIa with a small molecule inhibitor===
+A selective, slow binding inhibitor of factor VIIa binds to a nonstandard active site conformation and attenuates thrombus formation in vivo.,Olivero AG, Eigenbrot C, Goldsmith R, Robarge K, Artis DR, Flygare J, Rawson T, Sutherlin DP, Kadkhodayan S, Beresini M, Elliott LO, DeGuzman GG, Banner DW, Ultsch M, Marzec U, Hanson SR, Refino C, Bunting S, Kirchhofer D J Biol Chem. 2005 Mar 11;280(10):9160-9. Epub 2005 Jan 4. PMID:15632123<ref>PMID:15632123</ref>
-{{ABSTRACT_PUBMED_15632123}}
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-==About this Structure==
+<div class="pdbe-citations 1ygc" style="background-color:#fffaf0;"></div>
-[[1ygc]] is a 2 chain structure of [[Factor VIIa]] 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=1YGC OCA].
 ==See Also==
-*[[Factor VIIa|Factor VIIa]]
+*[[Factor VIIa 3D structures|Factor VIIa 3D structures]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:015632123</ref><references group="xtra"/>
+__TOC__
-[[Category: Coagulation factor VIIa]]
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Artis, D R.]]
+[[Category: Large Structures]]
-[[Category: Bunting, S.]]
+[[Category: Artis DR]]
-[[Category: Eigenbrot, C.]]
+[[Category: Bunting S]]
-[[Category: Flygare, J.]]
+[[Category: Eigenbrot C]]
-[[Category: Goldsmith, R.]]
+[[Category: Flygare J]]
-[[Category: Kirchhofer, D.]]
+[[Category: Goldsmith R]]
-[[Category: Olivero, A G.]]
+[[Category: Kirchhofer D]]
-[[Category: Rawson, T.]]
+[[Category: Olivero AG]]
-[[Category: Refino, C.]]
+[[Category: Rawson T]]
-[[Category: Robarge, K.]]
+[[Category: Refino C]]
-[[Category: Hydrolase]]
+[[Category: Robarge K]]
-[[Category: Inverted oxy-anion hole]]