View source for 1jvq


==Crystal structure at 2.6A of the ternary complex between antithrombin, a P14-P8 reactive loop peptide, and an exogenous tetrapeptide==
<StructureSection load='1jvq' size='340' side='right'caption='[[1jvq]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1jvq]] is a 4 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=1JVQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1JVQ FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NDG:2-(ACETYLAMINO)-2-DEOXY-A-D-GLUCOPYRANOSE'>NDG</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1br8|1br8]]</div></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=1jvq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jvq OCA], [https://pdbe.org/1jvq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1jvq RCSB], [https://www.ebi.ac.uk/pdbsum/1jvq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1jvq ProSAT]</span></td></tr>
</table>
== Disease ==
[[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>  
== Function ==
[[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>  
== 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/jv/1jvq_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=1jvq ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Many of the late-onset dementias, including Alzheimer's disease and the prion encephalopathies, arise from the aberrant aggregation of individual proteins. The serpin family of serine protease inhibitors provides a well-defined structural example of such pathological aggregation, as its mutant variants readily form long-chain polymers, resulting in diseases ranging from thrombosis to dementia. The intermolecular linkages result from the insertion of the reactive site loop of one serpin molecule into the middle strand (s4A) position of the A beta-sheet of another molecule. We define here the structural requirements for small peptides to competitively bind to and block the s4A position to prevent this intermolecular linkage and polymerisation. The entry and anchoring of blocking-peptides is facilitated by the presence of a threonine which inserts into the site equivalent to P8 of s4A. But the critical requirement for small blocking-peptides is demonstrated in crystallographic structures of the complexes formed with selected tri- and tetrapeptides. These structures indicate that the binding is primarily due to the insertion of peptide hydrophobic side-chains into the P4 and P6 sites of s4A. The findings allow the rational design of synthetic blocking-peptides small enough to be suitable for mimetic design. This is demonstrated here with a tetrapeptide that preferentially blocks the polymerisation of a pathologically unstable serpin commonly present in people of European descent.

How small peptides block and reverse serpin polymerisation.,Zhou A, Stein PE, Huntington JA, Sivasothy P, Lomas DA, Carrell RW J Mol Biol. 2004 Sep 17;342(3):931-41. PMID:15342247<ref>PMID:15342247</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1jvq" style="background-color:#fffaf0;"></div>

==See Also==
*[[Antithrombin 3D structures|Antithrombin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Carrell, R W]]
[[Category: Huntington, J A]]
[[Category: Lomas, D A]]
[[Category: Stein, P E]]
[[Category: Zhou, A]]
[[Category: Beta-barrel]]
[[Category: Blood clotting]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Loop-sheet polymer]]