5hvh
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 5hvh is ON HOLD Authors: Zhou, X., Weeks, S.D., Strelkov, S.V., Declerck, P.J. Description: Crystal Structure of Thrombin-activatable Fibrinolysis ...) |
|||
| (5 intermediate revisions not shown.) | |||
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==Crystal Structure of Thrombin-activatable Fibrinolysis Inhibitor in Complex with two Inhibitory Nanobodies== | |
| + | <StructureSection load='5hvh' size='340' side='right'caption='[[5hvh]], [[Resolution|resolution]] 3.00Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5hvh]] is a 3 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=5HVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HVH 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]] 3Å</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=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=5hvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hvh OCA], [https://pdbe.org/5hvh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hvh RCSB], [https://www.ebi.ac.uk/pdbsum/5hvh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hvh 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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 5hvh" style="background-color:#fffaf0;"></div> |
| - | [[Category: Declerck | + | |
| - | [[Category: Strelkov | + | ==See Also== |
| - | [[Category: Weeks | + | *[[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]] | ||
Current revision
Crystal Structure of Thrombin-activatable Fibrinolysis Inhibitor in Complex with two Inhibitory Nanobodies
| |||||||||||
