ArticleBiochemistry2011
Crystal structures of prethrombin-2 reveal alternative conformations under identical solution conditions and the mechanism of zymogen activation.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed, 44 citations in OpenAlex.
- In vivo targeting of open prothrombin with the monoclonal antibody POmAb results in anticoagulation without excessive bleeding.Journal of thrombosis and haemostasis : JTH · 2026Article
- Factor XII Structure-Function Relationships.Seminars in thrombosis and hemostasis · 2024Review
- A systematic approach for evaluating the role of surface-exposed loops in trypsin-like serine proteases applied to the 170 loop in coagulation factor VIIa.Scientific reports · 2022Article
- Mechanisms of ligand binding.Biophysics reviews · 2020Review
- Role of the activation peptide in the mechanism of protein C activation.Scientific reports · 2020Article
- Roles of the clip domains of two protease zymogens in the coagulation cascade in horseshoe crabs.The Journal of biological chemistry · 2020Article
- Article
- Sodium-induced population shift drives activation of thrombin.Scientific reports · 2020Article
- Role of the I16-D194 ionic interaction in the trypsin fold.Scientific reports · 2019Article
- Residues W215, E217 and E192 control the allosteric E*-E equilibrium of thrombin.Scientific reports · 2019Article
- Discovery and characterization of 2 novel subpopulations of aPS/PT antibodies in patients at high risk of thrombosis.Blood advances · 2019Article
- Probing prothrombin structure by limited proteolysis.Scientific reports · 2019Article
- Interplay between conformational selection and zymogen activation.Scientific reports · 2018Article
- Structure of prothrombin in the closed form reveals new details on the mechanism of activation.Scientific reports · 2018Article
- Reversible covalent direct thrombin inhibitors.PloS one · 2018Article
- Non-canonical proteolytic activation of human prothrombin by subtilisin fromThe Journal of biological chemistry · 2017Article
- Induced Fit Is a Special Case of Conformational Selection.Biochemistry · 2017Article
- Structural Architecture of Prothrombin in Solution Revealed by Single Molecule Spectroscopy.The Journal of biological chemistry · 2016Article
- Structural transitions during prothrombin activation: On the importance of fragment 2.Biochimie · 2016Article
- Kinetic dissection of the pre-existing conformational equilibrium in the trypsin fold.The Journal of biological chemistry · 2015Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Prethrombin-2 is the immediate zymogen precursor of the clotting enzyme thrombin, which is generated upon cleavage at R15 and separation of the A chain and catalytic B chain. The X-ray structure of prethrombin-2 determined in the free form at 1.9 Å resolution shows the 215-217 segment collapsed into the active site and occluding 49% of the volume available for substrate binding. Remarkably, some of the crystals harvested from the same crystallization well, under identical solution conditions, diffract to 2.2 Å resolution in the same space group but produce a structure in which the 215-217 segment moves >5 Å and occludes 24% of the volume available for substrate binding. The two alternative conformations of prethrombin-2 have the side chain of W215 relocating >9 Å within the active site and are relevant to the allosteric E*-E equilibrium of the mature enzyme. Another unanticipated feature of prethrombin-2 bears on the mechanism of prothrombin activation. R15 is found buried within the protein in ionic interactions with E14e, D14l, and E18, thereby making its exposure to solvent necessary for proteolytic attack and conversion to thrombin. On the basis of this structural observation, we constructed the E14eA/D14lA/E18A triple mutant to reduce the level of electrostatic coupling with R15 and promote zymogen activation. The mutation causes prethrombin-2 to spontaneously convert to thrombin, without the need for the snake venom ecarin or the physiological prothrombinase complex.
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