Universität zu Köln

Baeuml, Charlotte A., George, Ajay Abisheck Paul, Schmitz, Thomas, Sommerfeld, Paul, Pietsch, Markus, Podsiadlowski, Lars, Steinmetzer, Torsten, Biswas, Arijit and Imhof, Diana (2020). Distinct 3-disulfide-bonded isomers of tridegin differentially inhibit coagulation factor XIIIa: The influence of structural stability on bioactivity. Eur. J. Med. Chem., 201. ISSY-LES-MOULINEAUX: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER. ISSN 1768-3254

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Abstract

Tridegin is a 66mer cysteine-rich coagulation factor XIIIa (FXIIIa) inhibitor from the giant amazon leech Haementeria ghiliann of yet unknown disulfide connectivity. This study covers the structural and functional characterization of five different 3-disulfide-bonded tridegin isomers. In addition to three previously identified isomers, one isomer containing the inhibitory cystine knot (ICK, knottin) motif, and one isomer with the leech antihemostatic protein (LAP) motif were synthesized in a regioselective manner. A fluorogenic enzyme activity assay revealed a positive correlation between the constriction of conformational flexibility in the N-terminal part of the peptide and the inhibitory potential towards FXIIIa with clear differences between the isomers. This observation was supported by molecular dynamics (MD) simulations and subsequent molecular docking studies. The presented results provide detailed structureactivity relationship studies of different tridegin disulfide isomers towards FXIIIa and reveal insights into the possibly existing native linkage compared to non-native disulfide tridegin species. (C) 2020 Elsevier Masson SAS. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Baeuml, Charlotte A. UNSPECIFIED UNSPECIFIED UNSPECIFIED George, Ajay Abisheck Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmitz, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Sommerfeld, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Pietsch, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Podsiadlowski, Lars UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinmetzer, Torsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Biswas, Arijit UNSPECIFIED UNSPECIFIED UNSPECIFIED Imhof, Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-322245
DOI:	10.1016/j.ejmech.2020.112474
Journal or Publication Title:	Eur. J. Med. Chem.
Volume:	201
Date:	2020
Publisher:	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Place of Publication:	ISSY-LES-MOULINEAUX
ISSN:	1768-3254
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language REGIOSELECTIVE FORMATION; TRANSGLUTAMINASE 2; DISULFIDE BONDS; ACTIVATION; DERIVATIVES; GROMACS; POTENT; FIBRONECTIN; CONOTOXINS; MECHANISM Multiple languages Chemistry, Medicinal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32224