Thrombin is generated from
prothrombin through cleavage at two sites by the
prothrombinase complex.
Prothrombinase is composed of a
protease, factor (f) Xa, and a cofactor, fVa, which interact on negatively charged
phospholipid surfaces and cleave
prothrombin into
thrombin 300 000 times faster than fXa alone. The balance between
bleeding and
thrombosis depends on the amount of
thrombin produced, and this in turn depends on the function of the
prothrombinase complex. How fXa and fVa interact and how improved
prothrombin processing is conferred are of critical importance for understanding healthy and pathological blood clotting. Until recently, little structural information was available, and molecular models were built on partial structures with assembly guided by biochemical data. Last year our group published a crystal structure of a
prothrombinase complex from the
venom of the Australian Eastern Brown snake (known as
Pseutarin C). Here we use the crystal structure of
Pseutarin C as a starting point for homology modelling and assembly of the full human
prothrombinase complex. The interface is complementary in shape and charge, and is consistent with much of the published biochemical data. The model of human
prothrombinase presented here provides a powerful resource for contextualizing previous data and for designing future experiments.