View source for 5hvf


==Crystal Structure of Thrombin-activatable Fibrinolysis Inhibitor in Complex with an Inhibitory Nanobody (VHH-i83)==
<StructureSection load='5hvf' size='340' side='right'caption='[[5hvf]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5hvf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Vicugna_pacos Vicugna pacos]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HVF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HVF FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.85&#8491;</td></tr>
<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=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5hvf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hvf OCA], [https://pdbe.org/5hvf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hvf RCSB], [https://www.ebi.ac.uk/pdbsum/5hvf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hvf ProSAT]</span></td></tr>
</table>
== Function ==
[https://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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

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>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5hvf" style="background-color:#fffaf0;"></div>

==See Also==
*[[Antibody 3D structures|Antibody 3D structures]]
*[[Carboxypeptidase 3D structures|Carboxypeptidase 3D structures]]
*[[3D structures of non-human antibody|3D structures of non-human antibody]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Vicugna pacos]]
[[Category: Declerck PJ]]
[[Category: Strelkov SV]]
[[Category: Weeks SD]]
[[Category: Zhou X]]