title: Novel insights into structure and function of factor XIIIa-inhibitor tridegin.
abstract: The inhibition of the final step in blood coagulation, the factor XIIIa (FXIIIa) catalyzed cross-linking of fibrin monomers, is currently still a challenge in medicinal chemistry. We report synthesis, recombinant expression, disulfide connectivity, and biological activity of tridegin, the sole existing peptide representative displaying inhibitory activity on FXIIIa. Inhibition of the enzyme by this 66-mer cysteine-rich peptide is mediated by its C-terminal sequence, while the N-terminal part comprises structural information and contributes to inhibitor binding. Either of the production strategies examined leads to the formation of different disulfide-bridged isomers indicating the requirement of the correct fold for inhibitory activity. Molecular modeling and docking studies confirm disulfide bond isomer preference with respect to binding to FXIIIa, in turn, the knowledge of the enzyme-inhibitor interactions might bring about comprehensive ideas for the design of a suitable lead structure for addressing FXIIIa.
authors.affiliation: Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn , Brühler Str. 7, 53119 Bonn, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Böhm
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Bäuml
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hardes
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
authors.forename: Dirk
authors.initials: D
authors.lastname: Roeser
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schaub
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Than
authors.forename: Arijit
authors.initials: A
authors.lastname: Biswas
authors.forename: Diana
authors.initials: D
authors.lastname: Imhof
mesh_terms: D000595:Amino Acid Sequence; D002851:Chromatography, High Pressure Liquid; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D026122:Factor XIIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D012471:Salivary Proteins and Peptides / Q000737:chemistry* / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D004220:Disulfides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D012471:Salivary Proteins and Peptides; C106835:tridegin; D026122:Factor XIIIa