Model of a ternary complex between activated factor VII, tissue factor and factor IX

• Published in: Thrombosis and haemostasis Vol. 88; no. 1; p. 74
• Main Authors: Chen, Shu-wen W, Pellequer, Jean-Luc, Schved, Jean-François, Giansily-Blaizot, Muriel
• Format: Journal Article
• Language: English
• Published: Germany 01.07.2002
• Subjects: Algorithms; Binding Sites; Blood Coagulation Factors - chemistry; Blood Coagulation Factors - metabolism; Computer Simulation; Factor IX - chemistry; Factor IX - metabolism; Factor VIIa - chemistry; Factor VIIa - metabolism; Humans; Models, Molecular; Protein Binding; Protein Structure, Tertiary; Sequence Alignment; Thromboplastin - chemistry; Thromboplastin - metabolism
• ISSN: 0340-6245
• DOI: 10.1055/s-0037-1613157

Upon binding to tissue factor, FVIIa triggers coagulation by activating vitamin K-dependent zymogens, factor IX (FIX) and factor X (FX). To understand recognition mechanisms in the initiation step of the coagulation cascade, we present a three-dimensional model of the ternary complex between FVIIa:TF:FIX. This model was built using a full-space search algorithm in combination with computational graphics. With the known crystallographic complex FVIIa:TF kept fixed, the FIX docking was performed first with FIX Gla-EGF1 domains, followed by the FIX protease/EGF2 domains. Because the FIXa crystal structure lacks electron density for the Gla domain, we constructed a chimeric FIX molecule that contains the Gla-EGF1 domains of FVIIa and the EGF2-protease domains of FIXa. The FVIIa:TF:FIX complex has been extensively challenged against experimental data including site-directed mutagenesis, inhibitory peptide data, haemophilia B database mutations, inhibitor antibodies and a novel exosite binding inhibitor peptide. This FVIIa:TF:FIX complex provides a powerful tool to study the regulation of FVIIa production and presents new avenues for developing therapeutic inhibitory compounds of FVIIa:TF:substrate complex.