Crystal structure of the prothrombinase complex from the venom of Pseudonaja textilis

The prothrombinase complex, composed of the protease factor (f)Xa and cofactor fVa, efficiently converts prothrombin to thrombin by specific sequential cleavage at 2 sites. How the complex assembles and its mechanism of prothrombin processing are of central importance to human health and disease, be...

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Bibliographic Details
Published in:Blood 2013-10, Vol.122 (16), p.2777-2783
Main Authors: Lechtenberg, Bernhard C., Murray-Rust, Thomas A., Johnson, Daniel J.D., Adams, Ty E., Krishnaswamy, Sriram, Camire, Rodney M., Huntington, James A.
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Blood Coagulation
Crystallography, X-Ray
Elapid Venoms - chemistry
Factor V - chemistry
Factor Xa - chemistry
Humans
Models, Molecular
Mutation
Plenary Paper
Protein Conformation
Protein Structure, Tertiary
Snake Venoms - enzymology
Snakes
Thromboplastin - chemistry
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Summary:The prothrombinase complex, composed of the protease factor (f)Xa and cofactor fVa, efficiently converts prothrombin to thrombin by specific sequential cleavage at 2 sites. How the complex assembles and its mechanism of prothrombin processing are of central importance to human health and disease, because insufficient thrombin generation is the root cause of hemophilia, and excessive thrombin production results in thrombosis. Efforts to determine the crystal structure of the prothrombinase complex have been thwarted by the dependence of complex formation on phospholipid membrane association. Pseutarin C is an intrinsically stable prothrombinase complex preassembled in the venom gland of the Australian Eastern Brown Snake (Pseudonaja textilis). Here we report the crystal structures of the fX-fV complex and of activated fXa from P textilis venom and the derived model of active pseutarin C. Structural analysis supports a single substrate binding channel on fVa, to which prothrombin and the intermediate meizothrombin bind in 2 different orientations, providing insight into the architecture and mechanism of the prothrombinase complex—the molecular engine of blood coagulation. •The crystal structure of pro-pseutarin C reveals how the prothrombinase complex assembles and suggests a mechanism of prothrombin processing.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2013-06-511733