5hvg: Difference between revisions

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-'''Unreleased structure'''
-The entry 5hvg is ON HOLD  until Paper Publication
+==Crystal Structure of Thrombin-activatable Fibrinolysis Inhibitor in Complex with an Inhibitory Nanobody (VHH-a204)==
+<StructureSection load='5hvg' size='340' side='right'caption='[[5hvg]], [[Resolution|resolution]] 3.05&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5hvg]] is a 4 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=5HVG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HVG 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]] 3.05&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</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=5hvg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hvg OCA], [https://pdbe.org/5hvg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hvg RCSB], [https://www.ebi.ac.uk/pdbsum/5hvg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hvg 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.
-Authors: Zhou, X., Weeks, S.D., Strelkov, S.V., Declerck, P.J.
+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>
-Description: Crystal Structure of Thrombin-activatable Fibrinolysis Inhibitor in Complex with an Inhibitory Nanobody (VHH-a204)
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Zhou, X]]
+<div class="pdbe-citations 5hvg" style="background-color:#fffaf0;"></div>
-[[Category: Declerck, P.J]]
-[[Category: Strelkov, S.V]]
+==See Also==
-[[Category: Weeks, S.D]]
+*[[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]]