A Molecular Model of the Human Prothrombinase Complex

Everse, Stephen J.; Adams, Ty E.; Mann, Kenneth G.

doi:10.1007/978-4-431-78847-8_6

Cited by 3 publications

(6 citation statements)

References 162 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Three molecular models of human prothrombinase have been published previously (Autin et al, 2006;Everse et al, 2008;Lee et al, 2011). Autin et al (2006) published the first human prothrombinase model.…”

Section: Comparison To Previous Models Of Human Prothrombinasementioning

confidence: 99%

“…The prothrombinase model published by Everse et al (2008) was created using applied energy minimisation followed by protein-protein docking studies using a fVa model (constructed on bovine fVai, with the A2 domain modelled and placed as in ceruloplasmin) as a receptor molecule and a full-length fXa model (organised as in porcine fIXa) as a pseudo-ligand. Their resulting models were then filtered for consistency with biochemical results and for orientation of the C-domains and Gladomain for potential membrane interaction.…”

Section: Comparison To Previous Models Of Human Prothrombinasementioning

confidence: 99%

“…Brought to you by | University of Georgia Libraries Authenticated Download Date | 5/30/15 6:05 AM hope of obtaining insight into its assembly and function (Autin et al, 2006;Everse et al, 2008;Lee et al, 2008;Lee et al, 2011). However, as there was no crystal structure of an assembled complex available, these models were based on incomplete structural information, in silico docking algorithms, and guided by mutagenesis and other biochemical studies.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Homology model of human prothrombinase based on the crystal structure of Pseutarin C

Pomowski

Üstok

Huntington

2014

Biological Chemistry

View full text Add to dashboard Cite

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.

show abstract

Section: Comparison To Previous Models Of Human Prothrombinasementioning

confidence: 99%

Section: Comparison To Previous Models Of Human Prothrombinasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Homology model of human prothrombinase based on the crystal structure of Pseutarin C

Pomowski

Üstok

Huntington

2014

Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…37 We are now able to address the issue of prothrombin docking and sequential cleavage in a structurally directed manner. An important and interesting observation from our structure is that the active site of fXa is pointing away from the membrane toward the A1-A2 domain interface (up and to the left in the orientation shown in Figure 2A, left), suggesting that Pre1 docks on the ledge formed by the A1 and A2 domains and the connecting a1 loop.…”

Section: Location Of the Prothrombin Binding Sitementioning

confidence: 99%

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

Lechtenberg

Murray-Rust

Johnson

et al. 2013

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…Analysis of the proposed structural models of the prothrombinase complex allows for the possibility that Arg 306 is susceptible to APC in the FXaFVa i 506 complex [ 52 - 54 ]. The prothrombinase complex models differ in the orientation of FXa relative to FVa, and the binding interface between enzyme and cofactor.…”

Section: Resultsmentioning

confidence: 99%

Modeling of human factor Va inactivation by activated protein C

et al. 2012

View full text Add to dashboard Cite

BackgroundBecause understanding of the inventory, connectivity and dynamics of the components characterizing the process of coagulation is relatively mature, it has become an attractive target for physiochemical modeling. Such models can potentially improve the design of therapeutics. The prothrombinase complex (composed of the protease factor (F)Xa and its cofactor FVa) plays a central role in this network as the main producer of thrombin, which catalyses both the activation of platelets and the conversion of fibrinogen to fibrin, the main substances of a clot. A key negative feedback loop that prevents clot propagation beyond the site of injury is the thrombin-dependent generation of activated protein C (APC), an enzyme that inactivates FVa, thus neutralizing the prothrombinase complex. APC inactivation of FVa is complex, involving the production of partially active intermediates and “protection” of FVa from APC by both FXa and prothrombin. An empirically validated mathematical model of this process would be useful in advancing the predictive capacity of comprehensive models of coagulation.ResultsA model of human APC inactivation of prothrombinase was constructed in a stepwise fashion by analyzing time courses of FVa inactivation in empirical reaction systems with increasing number of interacting components and generating corresponding model constructs of each reaction system. Reaction mechanisms, rate constants and equilibrium constants informing these model constructs were initially derived from various research groups reporting on APC inactivation of FVa in isolation, or in the presence of FXa or prothrombin. Model predictions were assessed against empirical data measuring the appearance and disappearance of multiple FVa degradation intermediates as well as prothrombinase activity changes, with plasma proteins derived from multiple preparations. Our work integrates previously published findings and through the cooperative analysis of in vitro experiments and mathematical constructs we are able to produce a final validated model that includes 24 chemical reactions and interactions with 14 unique rate constants which describe the flux in concentrations of 24 species.ConclusionThis study highlights the complexity of the inactivation process and provides a module of equations describing the Protein C pathway that can be integrated into existing comprehensive mathematical models describing tissue factor initiated coagulation.

show abstract

A Molecular Model of the Human Prothrombinase Complex

Cited by 3 publications

References 162 publications

Homology model of human prothrombinase based on the crystal structure of Pseutarin C

Homology model of human prothrombinase based on the crystal structure of Pseutarin C

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

Modeling of human factor Va inactivation by activated protein C

Contact Info

Product

Resources

About