1. Model of a ternary complex between activated factor VII, tissue factor and factor IX.
- Author
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Chen SW, Pellequer JL, Schved JF, and Giansily-Blaizot M
- Subjects
- Algorithms, Binding Sites, Computer Simulation, Factor IX chemistry, Factor IX metabolism, Factor VIIa chemistry, Factor VIIa metabolism, Humans, Protein Binding, Protein Structure, Tertiary, Sequence Alignment, Thromboplastin chemistry, Thromboplastin metabolism, Blood Coagulation Factors chemistry, Blood Coagulation Factors metabolism, Models, Molecular
- Abstract
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.
- Published
- 2002