1e03

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[[Image:1e03.gif|left|200px]]
 
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{{Structure
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==PLASMA ALPHA ANTITHROMBIN-III AND PENTASACCHARIDE==
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|PDB= 1e03 |SIZE=350|CAPTION= <scene name='initialview01'>1e03</scene>, resolution 2.9&Aring;
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<StructureSection load='1e03' size='340' side='right'caption='[[1e03]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NTP:HEPARIN+PENTASACCHARIDE'>NTP</scene>
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<table><tr><td colspan='2'>[[1e03]] 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=1E03 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1E03 FirstGlance]. <br>
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|ACTIVITY=
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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]] 2.9&#8491;</td></tr>
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|GENE=
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=GU1:2,3-DI-O-METHYL-BETA-D-GLUCOPYRANURONIC+ACID'>GU1</scene>, <scene name='pdbligand=GU6:2,3,6-TRI-O-SULFONATO-ALPHA-D-GLUCOPYRANOSE'>GU6</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=Z9H:[(2S,3R,4S,5R,6R)-4,5-dimethoxy-2-oxidanyl-6-(sulfooxymethyl)oxan-3-yl]+hydrogen+sulfate'>Z9H</scene>, <scene name='pdbligand=Z9K:3-O-methyl-2-O-sulfo-alpha-L-idopyranuronic+acid'>Z9K</scene>, <scene name='pdbligand=Z9L:[(2R,3R,4S,5R,6S)-6-methoxy-3-oxidanyl-4,5-disulfooxy-oxan-2-yl]methyl+hydrogen+sulfate'>Z9L</scene></td></tr>
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|DOMAIN=
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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=1e03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e03 OCA], [https://pdbe.org/1e03 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1e03 RCSB], [https://www.ebi.ac.uk/pdbsum/1e03 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1e03 ProSAT]</span></td></tr>
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|RELATEDENTRY=
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1e03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e03 OCA], [http://www.ebi.ac.uk/pdbsum/1e03 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1e03 RCSB]</span>
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== Disease ==
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}}
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[https://www.uniprot.org/uniprot/ANT3_HUMAN ANT3_HUMAN] Defects in SERPINC1 are the cause of antithrombin III deficiency (AT3D) [MIM:[https://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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== Function ==
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[https://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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== 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/e0/1e03_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=1e03 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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Antithrombin is a member of the serpin family of protease inhibitors and the major inhibitor of the blood coagulation cascade. It is unique amongst the serpins in that it circulates in a conformation that is inactive against its target proteases. Activation of antithrombin is brought about by a conformational change initiated upon binding heparin or heparan sulphate. Two isoforms exist in the circulation, alpha-antithrombin and beta-antithrombin, which differ in the amount of glycosylation present on the polypeptide chain; beta-antithrombin lacks the carbohydrate present at Asn135 in alpha-antithrombin. Of the two forms, beta-antithrombin has the higher affinity for heparin and thus functions as the major inhibitor in vivo even though it is the less abundant form. The reason for the differences in heparin affinity between the alpha and beta-forms have been shown to be due to the additional carbohydrate changing the rate of the conformational change. Here, we describe the most accurate structures of alpha-antithrombin and alpha-antithrombin+heparin pentasaccharide reported to date (2.6A and 2.9A resolution, respectively, both re-refinements using old data), and the structure of beta-antithrombin (2.6A resolution). The new structures have a remarkable degree of ordered carbohydrate and include parts of the antithrombin chain not modeled before. The structures have allowed a detailed comparison of the conformational differences between the three. They show that the structural basis of the lower affinity for heparin of alpha-antithrombin over beta-antithrombin is due to the conformational change that occurs upon heparin binding being sterically hindered by the presence of the additional bulky carbohydrate at Asn135.
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'''PLASMA ALPHA ANTITHROMBIN-III AND PENTASACCHARIDE'''
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Structure of beta-antithrombin and the effect of glycosylation on antithrombin's heparin affinity and activity.,McCoy AJ, Pei XY, Skinner R, Abrahams JP, Carrell RW J Mol Biol. 2003 Feb 21;326(3):823-33. PMID:12581643<ref>PMID:12581643</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 1e03" style="background-color:#fffaf0;"></div>
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==Overview==
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==See Also==
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Antithrombin, a plasma serpin, is relatively inactive as an inhibitor of the coagulation proteases until it binds to the heparan side chains that line the microvasculature. The binding specifically occurs to a core pentasaccharide present both in the heparans and in their therapeutic derivative heparin. The accompanying conformational change of antithrombin is revealed in a 2.9-A structure of a dimer of latent and active antithrombins, each in complex with the high-affinity pentasaccharide. Inhibitory activation results from a shift in the main sheet of the molecule from a partially six-stranded to a five-stranded form, with extrusion of the reactive center loop to give a more exposed orientation. There is a tilting and elongation of helix D with the formation of a 2-turn helix P between the C and D helices. Concomitant conformational changes at the heparin binding site explain both the initial tight binding of antithrombin to the heparans and the subsequent release of the antithrombin-protease complex into the circulation. The pentasaccharide binds by hydrogen bonding of its sulfates and carboxylates to Arg-129 and Lys-125 in the D-helix, to Arg-46 and Arg-47 in the A-helix, to Lys-114 and Glu-113 in the P-helix, and to Lys-11 and Arg-13 in a cleft formed by the amino terminus. This clear definition of the binding site will provide a structural basis for developing heparin analogues that are more specific toward their intended target antithrombin and therefore less likely to exhibit side effects.
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*[[Antithrombin 3D structures|Antithrombin 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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1E03 is a [[Single protein]] structure of 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=1E03 OCA].
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__TOC__
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</StructureSection>
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==Reference==
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The anticoagulant activation of antithrombin by heparin., Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW, Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14683-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9405673 9405673]
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[[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: Abrahams, J P.]]
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[[Category: Abrahams J-P]]
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[[Category: Carrell, R W.]]
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[[Category: Carrell RW]]
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[[Category: Jin, L.]]
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[[Category: Jin L]]
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[[Category: Mccoy, A J.]]
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[[Category: McCoy AJ]]
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[[Category: Skinner, R.]]
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[[Category: Skinner R]]
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[[Category: serpin]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:52:17 2008''
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Current revision

PLASMA ALPHA ANTITHROMBIN-III AND PENTASACCHARIDE

PDB ID 1e03

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