Model of a Ternary Complex between Activated Factor VII, Tissue Factor and Factor IX

Shu-wen W. Chen; Jean-Luc Pellequer; Jean-François Schved; Muriel Giansily-Blaizot

doi:10.1055/s-0037-1613157

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2002; 88(01): 74-82
DOI: 10.1055/s-0037-1613157

Review Article

Schattauer GmbH

Model of a Ternary Complex between Activated Factor VII, Tissue Factor and Factor IX

Shu-wen W. Chen

,

Jean-Luc Pellequer

¹CEA Valrhô – Site de Marcoule. DSV/DIEP/SBTN, Bagnols-sur-Cèze, France

²The Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA

,

Jean-François Schved

³Laboratoire d’hématologie, CHU Saint-Eloi, Montpellier, France

,

Muriel Giansily-Blaizot

³Laboratoire d’hématologie, CHU Saint-Eloi, Montpellier, France

› Author Affiliations

Abstract

Summary

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.

Keywords

Protein-protein interaction - haemostasis - coagulation cascade - haemophilia - extrinsic pathway - comparative modeling - homology modelling

Full Text

References

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