5hvh

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'''Unreleased structure'''
 
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The entry 5hvh is ON HOLD until Paper Publication
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==Crystal Structure of Thrombin-activatable Fibrinolysis Inhibitor in Complex with two Inhibitory Nanobodies==
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<StructureSection load='5hvh' size='340' side='right' caption='[[5hvh]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5hvh]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HVH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HVH FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5hvf|5hvf]], [[5hvg|5hvg]]</td></tr>
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<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>
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<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=5hvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hvh OCA], [http://pdbe.org/5hvh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hvh RCSB], [http://www.ebi.ac.uk/pdbsum/5hvh PDBsum]</span></td></tr>
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</table>
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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BACKGROUND: Thrombin-activatable fibrinolysis inhibitor (TAFI) is activated to TAFIa by thrombin, plasmin or by the thrombin-thrombomodulin (T/TM) complex. TAFIa is antifibrinolytic and high levels of TAFIa constitute an increased risk for cardiovascular disorders. TAFI inhibitory nanobodies represent a promising approach in developing profibrinolytic therapeutics. OBJECTIVE: To elucidate the molecular mechanisms of inhibition of TAFI activation and TAFIa activity by nanobodies using X-ray crystallography and biochemical characterization. METHODS AND RESULTS: We selected two nanobodies for co-crystallization with TAFI. VHH-a204 interferes with all TAFI activation modes, whereas VHH-i83 interferes with T/TM-mediated activation and also inhibits TAFIa activity. The 3.05 A resolution crystal structure of TAFI/VHH-a204 reveals that VHH-a204 epitope is localized to the catalytic moiety (CM) in close proximity to the TAFI activation site at Arg92, indicating that VHH-a204 inhibits TAFI activation by steric hindrance. The 2.85 A resolution crystal structure of TAFI/VHH-i83 reveals that the VHH-i83 epitope is located close to the presumptive TM-binding site in the activation peptide (AP). The structure and supporting biochemical assays suggest that VHH-i83 inhibits TAFIa by bridging the AP to the CM following TAFI activation. In addition, the 3.00 A resolution crystal structure of the triple TAFI/VHH-a204/VHH-i83 complex demonstrates that the two nanobodies can simultaneously bind to TAFI. CONCLUSIONS: This study provides detailed insights into the molecular mechanisms of TAFI inhibition and reveals a novel mode of TAFIa inhibition. VHH-a204 and VHH-i83 merit further evaluation as potential profibrinolytic therapeutics. This article is protected by copyright. All rights reserved.
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Authors: Zhou, X., Weeks, S.D., Strelkov, S.V., Declerck, P.J.
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Elucidation of the molecular mechanisms of two nanobodies that inhibit TAFI activation and TAFIa activity.,Zhou X, Weeks SD, Ameloot P, Callewaert N, Strelkov SV, Declerck PJ J Thromb Haemost. 2016 Jun 9. doi: 10.1111/jth.13381. PMID:27279497<ref>PMID:27279497</ref>
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Description: Crystal Structure of Thrombin-activatable Fibrinolysis Inhibitor in Complex with two Inhibitory Nanobodies
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 5hvh" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Carboxypeptidase U]]
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[[Category: Declerck, P J]]
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[[Category: Strelkov, S V]]
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[[Category: Weeks, S D]]
[[Category: Zhou, X]]
[[Category: Zhou, X]]
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[[Category: Declerck, P.J]]
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[[Category: Antibody fragment]]
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[[Category: Strelkov, S.V]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Weeks, S.D]]
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[[Category: Hydrolase/hydrolase inhibitor]]
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[[Category: Nanobody]]
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[[Category: Plasma procarboxypeptidase b]]
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[[Category: Procarboxypeptidase r]]
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[[Category: Procarboxypeptidase u]]
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[[Category: Protein complex]]
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[[Category: Tafi]]
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[[Category: Thrombin-activatable fibrinolysis inhibitor]]

Revision as of 23:13, 23 June 2016

Crystal Structure of Thrombin-activatable Fibrinolysis Inhibitor in Complex with two Inhibitory Nanobodies

5hvh, resolution 3.00Å

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