Model of a ternary complex between activated factor VII, tissue factor and factor IX.
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.
Chen
Shu-wen W
SW
CEA Valrhô-Site de Marcoule, DSV/DIEP/SBTN, Bagnols-sur-Cèze, France.
Pellequer
Jean-Luc
JL
Schved
Jean-François
JF
Giansily-Blaizot
Muriel
M
D000465:Algorithms; D001665:Binding Sites; D001779:Blood Coagulation Factors / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D005164:Factor IX / Q000737:chemistry / Q000378:metabolism; D015942:Factor VIIa / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013925:Thromboplastin / Q000737:chemistry / Q000378:metabolism
D001779:Blood Coagulation Factors; D005164:Factor IX; D013925:Thromboplastin; D015942:Factor VIIa