1dva

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(New page: 200px<br /> <applet load="1dva" size="450" color="white" frame="true" align="right" spinBox="true" caption="1dva, resolution 3.00&Aring;" /> '''CRYSTAL STRUCTURE O...)
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[[Image:1dva.gif|left|200px]]<br />
 
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<applet load="1dva" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1dva, resolution 3.00&Aring;" />
 
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'''CRYSTAL STRUCTURE OF THE COMPLEX BETWEEN THE PEPTIDE EXOSITE INHIBITOR E-76 AND COAGULATION FACTOR VIIA'''<br />
 
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==Overview==
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==Crystal Structure of the Complex Between the Peptide Exosite Inhibitor E-76 and Coagulation Factor VIIA==
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Potent anticoagulants have been derived by targeting the tissue, factor-factor VIIa complex with naive peptide libraries displayed on M13, phage. The peptides specifically block the activation of factor X with a, median inhibitory concentration of 1 nM and selectively inhibit, tissue-factor-dependent clotting. The peptides do not bind to the active, site of factor VIIa; rather, they work by binding to an exosite on the, factor VIIa protease domain, and non-competitively inhibit activation of, factor X and amidolytic activity. One such peptide (E-76) has a well, defined structure in solution determined by NMR spectroscopy that is, similar to the X-ray crystal structure when complexed with factor VIIa., These structural and functional studies indicate an allosteric 'switch', mechanism of inhibition involving an activation loop of factor VIIa and, represent a new framework for developing inhibitors of serine proteases.
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<StructureSection load='1dva' size='340' side='right'caption='[[1dva]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1dva]] is a 6 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=1DVA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DVA 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]] 3&#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=0Z6:D-PHENYLALANYL-N-[(2S,3S)-6-{[AMINO(IMINIO)METHYL]AMINO}-1-CHLORO-2-HYDROXYHEXAN-3-YL]-L-PHENYLALANINAMIDE'>0Z6</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=BGC:BETA-D-GLUCOSE'>BGC</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=FUL:BETA-L-FUCOSE'>FUL</scene>, <scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=PRD_900004:beta-lactose'>PRD_900004</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=1dva FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dva OCA], [https://pdbe.org/1dva PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1dva RCSB], [https://www.ebi.ac.uk/pdbsum/1dva PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1dva 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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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/dv/1dva_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1dva ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Potent anticoagulants have been derived by targeting the tissue factor-factor VIIa complex with naive peptide libraries displayed on M13 phage. The peptides specifically block the activation of factor X with a median inhibitory concentration of 1 nM and selectively inhibit tissue-factor-dependent clotting. The peptides do not bind to the active site of factor VIIa; rather, they work by binding to an exosite on the factor VIIa protease domain, and non-competitively inhibit activation of factor X and amidolytic activity. One such peptide (E-76) has a well defined structure in solution determined by NMR spectroscopy that is similar to the X-ray crystal structure when complexed with factor VIIa. These structural and functional studies indicate an allosteric 'switch' mechanism of inhibition involving an activation loop of factor VIIa and represent a new framework for developing inhibitors of serine proteases.
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==Disease==
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Peptide exosite inhibitors of factor VIIa as anticoagulants.,Dennis MS, Eigenbrot C, Skelton NJ, Ultsch MH, Santell L, Dwyer MA, O'Connell MP, Lazarus RA Nature. 2000 Mar 30;404(6777):465-70. PMID:10761907<ref>PMID:10761907</ref>
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Known diseases associated with this structure: Factor VII deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=227500 227500]], Myocardial infarction, decreased susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=227500 227500]]
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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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1DVA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with GLC, FUC, FUL, CA, CAC, ACE and CH2 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1DVA OCA].
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</div>
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<div class="pdbe-citations 1dva" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Peptide exosite inhibitors of factor VIIa as anticoagulants., Dennis MS, Eigenbrot C, Skelton NJ, Ultsch MH, Santell L, Dwyer MA, O'Connell MP, Lazarus RA, Nature. 2000 Mar 30;404(6777):465-70. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10761907 10761907]
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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: Single protein]]
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[[Category: Large Structures]]
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[[Category: Eigenbrot, C.]]
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[[Category: Eigenbrot C]]
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[[Category: Ultsch, M.H.]]
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[[Category: Ultsch MH]]
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[[Category: ACE]]
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[[Category: CA]]
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[[Category: CAC]]
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[[Category: CH2]]
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[[Category: FUC]]
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[[Category: FUL]]
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[[Category: GLC]]
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[[Category: protein-peptide complex]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:36:19 2007''
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Current revision

Crystal Structure of the Complex Between the Peptide Exosite Inhibitor E-76 and Coagulation Factor VIIA

PDB ID 1dva

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