New insight into how tissue factor allosterically regulates factor VIIa.
Factor VIIa (FVIIa) is the coagulation protease responsible for starting a cascade of proteolytic events that lead to thrombin generation, and hence, to fibrin deposition and platelet activation. As such, it has attracted interest as a target for clinical anticoagulant therapy. Commensurate with the critical importance of maintaining balance between thrombosis and hemostasis and FVIIa's place at the beginning of the coagulation process, FVIIa is subject to a variety of biological and biochemical control mechanisms, among them allosteric influences exerted by cofactors, substrates, and inhibitors. Essential for the proteolytic activity of FVIIa is its cofactor, Tissue Factor (TF). Major progress in elucidating the key influence of TF was made when the TF.FVIIa structure was determined in 1996. However, a molecular explanation of an important aspect of TF's influence-its effect on the active site-was not available until the recent determination of a FVII zymogen structure. In this review we discuss the significance of unprecedented differences between these two structures in understanding the regulation of this important enzyme.