Isolation, Co-Crystallization and Structure-Based Characterization of Anabaenopeptins as Highly Potent Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa).

2.50
Hdl Handle:
http://hdl.handle.net/10033/621048
Title:
Isolation, Co-Crystallization and Structure-Based Characterization of Anabaenopeptins as Highly Potent Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa).
Authors:
Schreuder, Herman; Liesum, Alexander; Lönze, Petra; Stump, Heike; Hoffmann, Holger; Schiell, Matthias; Kurz, Michael; Toti, Luigi; Bauer, Armin; Kallus, Christopher; Klemke-Jahn, Christine; Czech, Jörg; Kramer, Dan; Enke, Heike; Niedermeyer, Timo H J; Morrison, Vincent; Kumar, Vasant; Brönstrup, Mark ( 0000-0002-8971-7045 )
Abstract:
Mature thrombin activatable fibrinolysis inhibitor (TAFIa) is a carboxypeptidase that stabilizes fibrin clots by removing C-terminal arginines and lysines from partially degraded fibrin. Inhibition of TAFIa stimulates the degradation of fibrin clots and may help to prevent thrombosis. Applying a lead finding approach based on literature-mining, we discovered that anabaenopeptins, cyclic peptides produced by cyanobacteria, were potent inhibitors of TAFIa with IC50 values as low as 1.5 nM. We describe the isolation and structure elucidation of 20 anabaenopeptins, including 13 novel congeners, as well as their pronounced structure-activity relationships (SAR) with respect to inhibition of TAFIa. Crystal structures of the anabaenopeptins B, C and F bound to the surrogate protease carboxypeptidase B revealed the binding modes of these large (~850 Da) compounds in detail and explained the observed SAR, i.e. the strong dependence of the potency on a basic (Arg, Lys) exocyclic residue that addressed the S1' binding pocket, and a broad tolerance towards substitutions in the pentacyclic ring that acted as a plug of the active site.
Affiliation:
Helmholtz Centre of infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
Isolation, Co-Crystallization and Structure-Based Characterization of Anabaenopeptins as Highly Potent Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa). 2016, 6:32958 Sci Rep
Journal:
Scientific reports
Issue Date:
8-Sep-2016
URI:
http://hdl.handle.net/10033/621048
DOI:
10.1038/srep32958
PubMed ID:
27604544
Type:
Article
Language:
en
ISSN:
2045-2322
Appears in Collections:
Publications of the research group Chemical Biology (CBIO)

Full metadata record

DC FieldValue Language
dc.contributor.authorSchreuder, Hermanen
dc.contributor.authorLiesum, Alexanderen
dc.contributor.authorLönze, Petraen
dc.contributor.authorStump, Heikeen
dc.contributor.authorHoffmann, Holgeren
dc.contributor.authorSchiell, Matthiasen
dc.contributor.authorKurz, Michaelen
dc.contributor.authorToti, Luigien
dc.contributor.authorBauer, Arminen
dc.contributor.authorKallus, Christopheren
dc.contributor.authorKlemke-Jahn, Christineen
dc.contributor.authorCzech, Jörgen
dc.contributor.authorKramer, Danen
dc.contributor.authorEnke, Heikeen
dc.contributor.authorNiedermeyer, Timo H Jen
dc.contributor.authorMorrison, Vincenten
dc.contributor.authorKumar, Vasanten
dc.contributor.authorBrönstrup, Marken
dc.date.accessioned2017-08-04T13:09:03Z-
dc.date.available2017-08-04T13:09:03Z-
dc.date.issued2016-09-08-
dc.identifier.citationIsolation, Co-Crystallization and Structure-Based Characterization of Anabaenopeptins as Highly Potent Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa). 2016, 6:32958 Sci Repen
dc.identifier.issn2045-2322-
dc.identifier.pmid27604544-
dc.identifier.doi10.1038/srep32958-
dc.identifier.urihttp://hdl.handle.net/10033/621048-
dc.description.abstractMature thrombin activatable fibrinolysis inhibitor (TAFIa) is a carboxypeptidase that stabilizes fibrin clots by removing C-terminal arginines and lysines from partially degraded fibrin. Inhibition of TAFIa stimulates the degradation of fibrin clots and may help to prevent thrombosis. Applying a lead finding approach based on literature-mining, we discovered that anabaenopeptins, cyclic peptides produced by cyanobacteria, were potent inhibitors of TAFIa with IC50 values as low as 1.5 nM. We describe the isolation and structure elucidation of 20 anabaenopeptins, including 13 novel congeners, as well as their pronounced structure-activity relationships (SAR) with respect to inhibition of TAFIa. Crystal structures of the anabaenopeptins B, C and F bound to the surrogate protease carboxypeptidase B revealed the binding modes of these large (~850 Da) compounds in detail and explained the observed SAR, i.e. the strong dependence of the potency on a basic (Arg, Lys) exocyclic residue that addressed the S1' binding pocket, and a broad tolerance towards substitutions in the pentacyclic ring that acted as a plug of the active site.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleIsolation, Co-Crystallization and Structure-Based Characterization of Anabaenopeptins as Highly Potent Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa).en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre of infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalScientific reportsen

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