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Biactivity of a peptide from a Leech

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AutorInnen: 
Imhof, D., Baeuml, C., George, A.A.P., Schmitz, T., Sommerfeld, P., Pietsch, M., Podsiadlowski, L., Steinmetzer, T., Biswas, A.
Erscheinungsjahr: 
2020
Vollständiger Titel: 
Distinct 3-disulfide-bonded isomers of tridegin differentially inhibit coagulation factor XIIIa: The influence of structural stability on bioactivity
ZFMK-Autorinnen / ZFMK-Autoren: 
Dr. Lars Podsiadlowski
Org. Einordnung: 
Molekularlabor, Zentrum für molekulare Biodiversitätsforschung (zmb)
Publikationstyp: 
Zeitschriftenaufsatz
DOI Name: 
https://doi.org/10.1016/j.ejmech.2020.112474
Bibliographische Angaben: 
Imhof, D., Baeuml, C., George, A.A.P., Schmitz, T., Sommerfeld, P., Pietsch, M., Podsiadlowski, L., Steinmetzer, T., Biswas, A. (2020): Distinct 3-disulfide-bonded isomers of tridegin differentially inhibit coagulation factor XIIIa: The influence of structural stability on bioactivity. Eur J Medicinal Chem. 201: 112472
Abstract: 

Tridegin is a 66mer cysteine-rich coagulation factor XIIIa (FXIIIa) inhibitor from the giant amazon leech Haementeria ghilianii 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 structure-activity 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.