2gd4

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{{STRUCTURE_2gd4| PDB=2gd4 | SCENE= }}
 
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===Crystal Structure of the Antithrombin-S195A Factor Xa-Pentasaccharide Complex===
 
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{{ABSTRACT_PUBMED_16619025}}
 
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==Disease==
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==Crystal Structure of the Antithrombin-S195A Factor Xa-Pentasaccharide Complex==
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[[http://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN]] Defects in F10 are the cause of factor X deficiency (FA10D) [MIM:[http://omim.org/entry/227600 227600]]. A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis.<ref>PMID:2790181</ref><ref>PMID:1973167</ref><ref>PMID:1985698</ref><ref>PMID:7669671</ref><ref>PMID:8529633</ref><ref>PMID:7860069</ref><ref>PMID:8845463</ref><ref>PMID:8910490</ref><ref>PMID:10468877</ref><ref>PMID:10746568</ref><ref>PMID:10739379</ref><ref>PMID:11248282</ref><ref>PMID:11728527</ref><ref>PMID:12945883</ref><ref>PMID:15650540</ref><ref>PMID:17393015</ref><ref>PMID:19135706</ref> [[http://www.uniprot.org/uniprot/ANT3_HUMAN ANT3_HUMAN]] Defects in SERPINC1 are the cause of antithrombin III deficiency (AT3D) [MIM:[http://omim.org/entry/613118 613118]]. AT3D is an important risk factor for hereditary thrombophilia, a hemostatic disorder characterized by a tendency to recurrent thrombosis. AT3D is classified into 4 types. Type I: characterized by a 50% decrease in antigenic and functional levels. Type II: has defects affecting the thrombin-binding domain. Type III: alteration of the heparin-binding domain. Plasma AT-III antigen levels are normal in type II and III. Type IV: consists of miscellaneous group of unclassifiable mutations.<ref>PMID:7734359</ref>[:]<ref>PMID:3191114</ref><ref>PMID:9031473</ref><ref>PMID:6582486</ref><ref>PMID:3080419</ref><ref>PMID:3805013</ref><ref>PMID:3179438</ref><ref>PMID:3162733</ref><ref>PMID:2781509</ref><ref>PMID:2365065</ref><ref>PMID:2229057</ref><ref>PMID:2013320</ref><ref>PMID:1906811</ref><ref>PMID:1555650</ref><ref>PMID:1547341</ref><ref>PMID:8443391</ref><ref>PMID:8486379</ref><ref>PMID:7981186</ref><ref>PMID:7959685</ref><ref>PMID:8274732</ref><ref>PMID:7994035</ref><ref>PMID:7989582</ref>[:]<ref>PMID:7878627</ref><ref>PMID:7832187</ref><ref>PMID:9157604</ref><ref>PMID:9845533</ref><ref>PMID:9759613</ref><ref>PMID:10997988</ref><ref>PMID:11794707</ref><ref>PMID:11713457</ref><ref>PMID:12353073</ref><ref>PMID:12595305</ref><ref>PMID:12894857</ref><ref>PMID:15164384</ref><ref>PMID:16908819</ref>
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<StructureSection load='2gd4' size='340' side='right'caption='[[2gd4]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2gd4]] 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=2GD4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GD4 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]] 3.3&#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=BDP:BETA-D-GLUCOPYRANURONIC+ACID'>BDP</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=IDS:2-O-SULFO-ALPHA-L-IDOPYRANURONIC+ACID'>IDS</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PRD_900028:fondaparinux'>PRD_900028</scene>, <scene name='pdbligand=SGN:N,O6-DISULFO-GLUCOSAMINE'>SGN</scene>, <scene name='pdbligand=SUS:2-DEOXY-3,6-DI-O-SULFO-2-(SULFOAMINO)-ALPHA-D-GLUCOPYRANOSE'>SUS</scene>, <scene name='pdbligand=ZDO:[(2S,3R,4R,5S,6R)-2-methoxy-4,5-bis(oxidanyl)-6-(sulfooxymethyl)oxan-3-yl]sulfamic+acid'>ZDO</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=2gd4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gd4 OCA], [https://pdbe.org/2gd4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gd4 RCSB], [https://www.ebi.ac.uk/pdbsum/2gd4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gd4 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN] Defects in F10 are the cause of factor X deficiency (FA10D) [MIM:[https://omim.org/entry/227600 227600]. A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis.<ref>PMID:2790181</ref> <ref>PMID:1973167</ref> <ref>PMID:1985698</ref> <ref>PMID:7669671</ref> <ref>PMID:8529633</ref> <ref>PMID:7860069</ref> <ref>PMID:8845463</ref> <ref>PMID:8910490</ref> <ref>PMID:10468877</ref> <ref>PMID:10746568</ref> <ref>PMID:10739379</ref> <ref>PMID:11248282</ref> <ref>PMID:11728527</ref> <ref>PMID:12945883</ref> <ref>PMID:15650540</ref> <ref>PMID:17393015</ref> <ref>PMID:19135706</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN] Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
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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/gd/2gd4_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=2gd4 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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Regulation of blood coagulation is critical for maintaining blood flow, while preventing excessive bleeding or thrombosis. One of the principal regulatory mechanisms involves heparin activation of the serpin antithrombin (AT). Inhibition of several coagulation proteases is accelerated by up to 10,000-fold by heparin, either through bridging AT and the protease or by inducing allosteric changes in the properties of AT. The anticoagulant effect of short heparin chains, including the minimal AT-specific pentasaccharide, is mediated exclusively through the allosteric activation of AT towards efficient inhibition of coagulation factors (f) IXa and Xa. Here we present the crystallographic structure of the recognition (Michaelis) complex between heparin-activated AT and S195A fXa, revealing the extensive exosite contacts that confer specificity. The heparin-induced conformational change in AT is required to allow simultaneous contacts within the active site and two distinct exosites of fXa (36-loop and the autolysis loop). This structure explains the molecular basis of protease recognition by AT, and the mechanism of action of the important therapeutic low-molecular-weight heparins.
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==Function==
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Antithrombin-S195A factor Xa-heparin structure reveals the allosteric mechanism of antithrombin activation.,Johnson DJ, Li W, Adams TE, Huntington JA EMBO J. 2006 May 3;25(9):2029-37. Epub 2006 Apr 13. PMID:16619025<ref>PMID:16619025</ref>
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[[http://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN]] Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting. [[http://www.uniprot.org/uniprot/ANT3_HUMAN ANT3_HUMAN]] Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory activity is greatly enhanced in the presence of heparin.<ref>PMID:15853774</ref>
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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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[[2gd4]] is a 6 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=2GD4 OCA].
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</div>
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<div class="pdbe-citations 2gd4" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==
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*[[Antithrombin|Antithrombin]]
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*[[Antithrombin 3D structures|Antithrombin 3D structures]]
*[[Factor Xa|Factor Xa]]
*[[Factor Xa|Factor Xa]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:016619025</ref><references group="xtra"/><references/>
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__TOC__
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[[Category: Coagulation factor Xa]]
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Adams, T E.]]
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[[Category: Large Structures]]
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[[Category: Huntington, J A.]]
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[[Category: Adams TE]]
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[[Category: Johnson, D J.]]
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[[Category: Huntington JA]]
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[[Category: Li, W.]]
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[[Category: Johnson DJ]]
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[[Category: Hydrolase]]
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[[Category: Li W]]
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[[Category: Michaelis complex]]
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[[Category: Serpin]]
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Current revision

Crystal Structure of the Antithrombin-S195A Factor Xa-Pentasaccharide Complex

PDB ID 2gd4

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