ArticleThe Journal of biological chemistry2013
Crystal structure of prothrombin reveals conformational flexibility and mechanism of activation.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- Structural basis for the procoagulant activity ofBiological chemistry · 2026Review
- Molecular mechanism of cleavage at R271 during prothrombin activation revealed by cryo-EM.Blood · 2026Article
- Prothrombinase processivity is conferred by substrate allostery.The EMBO journal · 2026Article
- Protein Induced by Vitamin K Absence or Antagonist II in Primary Liver Cancer: Basic Research Insights and Clinical Applications.Journal of clinical and translational hepatology · 2025Review
- Article
- The Prothrombin-Prothrombinase Interaction.Sub-cellular biochemistry · 2024Review
- Regulation of Peptidase Activity beyond the Active Site in Human Health and Disease.International journal of molecular sciences · 2023Review
- Super-high procoagulant activity of gecko thrombin: A gift from sky dragon.CNS neuroscience & therapeutics · 2023Article
- Cryo-EM structures of coagulation factors.Research and practice in thrombosis and haemostasis · 2022Review
- Article
- Exosite Binding in Thrombin: A Global Structural/Dynamic Overview of Complexes with Aptamers and Other Ligands.International journal of molecular sciences · 2021Review
- Progression of Prothrombin Induced by Vitamin K Absence-II in Hepatocellular Carcinoma.Frontiers in oncology · 2021Review
- Residues W215, E217 and E192 control the allosteric E*-E equilibrium of thrombin.Scientific reports · 2019Article
- Probing prothrombin structure by limited proteolysis.Scientific reports · 2019Article
- Thrombin Exosite Maturation and Ligand Binding at ABE II Help Stabilize PAR-Binding Competent Conformation at ABE I.Biochemistry · 2019Article
- The Complex Fibrinogen Interactions of theFrontiers in cellular and infection microbiology · 2019Article
- Enhancing the anticoagulant profile of meizothrombin.Biomolecular concepts · 2018Article
- Interplay between conformational selection and zymogen activation.Scientific reports · 2018Article
- Deciphering Conformational Changes Associated with the Maturation of Thrombin Anion Binding Exosite I.Biochemistry · 2017Article
- Clinical application of protein induced by vitamin K antagonist-II as a biomarker in hepatocellular carcinoma.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Review
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6 authors.
Funding
Abstract
The zymogen prothrombin is composed of fragment 1 containing a Gla domain and kringle-1, fragment 2 containing kringle-2, and a protease domain containing A and B chains. The prothrombinase complex assembled on the surface of platelets converts prothrombin to thrombin by cleaving at Arg-271 and Arg-320. The three-dimensional architecture of prothrombin and the molecular basis of its activation remain elusive. Here we report the first x-ray crystal structure of prothrombin as a Gla-domainless construct carrying an Ala replacement of the catalytic Ser-525. Prothrombin features a conformation 80 Å long, with fragment 1 positioned at a 36° angle relative to the main axis of fragment 2 coaxial to the protease domain. High flexibility of the linker connecting the two kringles suggests multiple arrangements for kringle-1 relative to the rest of the prothrombin molecule. Luminescence resonance energy transfer measurements detect two distinct conformations of prothrombin in solution, in a 3:2 ratio, with the distance between the two kringles either fully extended (54 ± 2 Å) or partially collapsed (≤34 Å) as seen in the crystal structure. A molecular mechanism of prothrombin activation emerges from the structure. Of the two sites of cleavage, Arg-271 is located in a disordered region connecting kringle-2 to the A chain, but Arg-320 is well defined within the activation domain and is not accessible to proteolysis in solution. Burial of Arg-320 prevents prothrombin autoactivation and directs prothrombinase to cleave at Arg-271 first. Reversal of the local electrostatic potential then redirects prothrombinase toward Arg-320, leading to thrombin generation via the prethrombin-2 intermediate.
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