title: Homology model of human prothrombinase based on the crystal structure of Pseutarin C.
abstract: 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.
authors.forename: Anja
authors.initials: A
authors.lastname: Pomowski
authors.forename: Fatma Isik
authors.initials: FI
authors.lastname: Ustok
authors.forename: James A
authors.initials: JA
authors.lastname: Huntington
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004546:Elapid Venoms / Q000737:chemistry*; D005165:Factor V / Q000737:chemistry*; D015943:Factor Va / Q000737:chemistry; D015951:Factor Xa / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D012911:Snakes
chemical_list: D004546:Elapid Venoms; C475049:Pseutarin C; C022475:prothrombinase complex; D015943:Factor Va; D005165:Factor V; D015951:Factor Xa