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5hvh

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Revision as of 02:27, 13 July 2016

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

Structural highlights

5hvh is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	5hvf, 5hvg
Activity:	Carboxypeptidase U, with EC number 3.4.17.20
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1]

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mao SS, Cooper CM, Wood T, Shafer JA, Gardell SJ. Characterization of plasmin-mediated activation of plasma procarboxypeptidase B. Modulation by glycosaminoglycans. J Biol Chem. 1999 Dec 3;274(49):35046-52. PMID:10574983
↑ Zhou X, Weeks SD, Ameloot P, Callewaert N, Strelkov SV, Declerck PJ. Elucidation of the molecular mechanisms of two nanobodies that inhibit TAFI activation and TAFIa activity. J Thromb Haemost. 2016 Jun 9. doi: 10.1111/jth.13381. PMID:27279497 doi:http://dx.doi.org/10.1111/jth.13381

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5hvh"

@@ Line 7: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5hvf|5hvf]], [[5hvg|5hvg]]</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=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>
+<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], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hvh ProSAT]</span></td></tr>
 </table>
 == Function ==

5hvh

From Proteopedia

Revision as of 02:27, 13 July 2016

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

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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