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{{STRUCTURE_3lms|  PDB=3lms  |  SCENE=  }}
==Structure of human activated thrombin-activatable fibrinolysis inhibitor, TAFIa, in complex with tick-derived funnelin inhibitor, TCI.==
===Structure of human activated thrombin-activatable fibrinolysis inhibitor, TAFIa, in complex with tick-derived funnelin inhibitor, TCI.===
<StructureSection load='3lms' size='340' side='right' caption='[[3lms]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
{{ABSTRACT_PUBMED_20088943}}
== Structural highlights ==
<table><tr><td colspan='2'>[[3lms]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Rhipicephalus_bursa Rhipicephalus bursa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3LMS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3LMS FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3d4u|3d4u]], [[3d6v|3d6v]], [[3d66|3d66]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carboxypeptidase_U Carboxypeptidase U], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.17.20 3.4.17.20] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3lms FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lms OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3lms RCSB], [http://www.ebi.ac.uk/pdbsum/3lms PDBsum]</span></td></tr>
</table>
== 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/lm/3lms_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/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
SUMMARY BACKGROUND: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a validated target for thrombotic diseases. TAFI is converted in vivo to activated TAFI (TAFIa) by removal of its pro-domain. Whereas TAFI is stable and persists in the circulation, possibly in complex with plasminogen, TAFIa is unstable and poorly soluble, with a half-life of minutes. OBJECTIVES: In order to study the molecular determinants of this instability, we studied the influence of protein inhibitors on human TAFIa. RESULTS: We found that protein inhibitors significantly reduced the instability and insolubility of TAFIa. In addition, we solved the 2.5-A resolution crystal structure of human TAFIa in complex with a potent protein inhibitor, tick-derived carboxypeptidase inhibitor, which gives rise to a stable and soluble TAFIa species. The structure revealed a significant reduction in the flexibility of dynamic segments when compared with the structures of bovine and human TAFI. We also identified two latent hotspots, loop Lbeta2beta3 and segment alpha5-Lalpha5beta7-beta7, where conformational destabilization may begin. These hotspots are also present in TAFI, but the pro-domain may provide sufficient stabilization and solubility to guarantee protein persistence in vivo. When the pro-domain is removed, the free TAFIa moiety becomes unstable, its activity is suppressed, and the molecule becomes insoluble. CONCLUSIONS: The present study corroborates the function of protein inhibitors in stabilizing human TAFIa and it provides a rigid and high-resolution mold for the design of small molecule inhibitors of this enzyme, thus paving the way for novel therapy for thrombotic disorders.


==Function==
Insights into the molecular inactivation mechanism of human activated thrombin-activatable fibrinolysis inhibitor.,Sanglas L, Arolas JL, Valnickova Z, Aviles FX, Enghild JJ, Gomis-Ruth FX J Thromb Haemost. 2010 May;8(5):1056-65. Epub 2010 Jan 17. PMID:20088943<ref>PMID:20088943</ref>
[[http://www.uniprot.org/uniprot/CBPB2_HUMAN CBPB2_HUMAN]] Cleaves C-terminal arginine or lysine residues from biologically active peptides such as kinins or anaphylatoxins in the circulation thereby regulating their activities. Down-regulates fibrinolysis by removing C-terminal lysine residues from fibrin that has already been partially degraded by plasmin.<ref>PMID:10574983</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[3lms]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Rhipicephalus_bursa Rhipicephalus bursa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3LMS OCA].
</div>


==Reference==
==See Also==
<ref group="xtra">PMID:020088943</ref><references group="xtra"/><references/>
*[[Carboxypeptidase|Carboxypeptidase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Carboxypeptidase U]]
[[Category: Carboxypeptidase U]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Rhipicephalus bursa]]
[[Category: Rhipicephalus bursa]]
[[Category: Arolas, J L.]]
[[Category: Arolas, J L]]
[[Category: Aviles, F X.]]
[[Category: Aviles, F X]]
[[Category: Enghild, J J.]]
[[Category: Enghild, J J]]
[[Category: Gomis-Ruth, F X.]]
[[Category: Gomis-Ruth, F X]]
[[Category: Sanglas, L.]]
[[Category: Sanglas, L]]
[[Category: Valnickova, Z.]]
[[Category: Valnickova, Z]]
[[Category: Alpha-beta-hydrolase]]
[[Category: Alpha-beta-hydrolase]]
[[Category: Blood coagulation]]
[[Category: Blood coagulation]]

Revision as of 15:31, 18 December 2014

Structure of human activated thrombin-activatable fibrinolysis inhibitor, TAFIa, in complex with tick-derived funnelin inhibitor, TCI.

3lms, resolution 2.50Å

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