ArticleScientific reports2018
Interplay between conformational selection and zymogen activation.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 23 citations in OpenAlex.
- Conformational Dynamics of Viral Protease Precursors in Maturation, Inhibition, and Drug-Resistance Development.Viruses · 2026Review
- Molecular mechanism of cleavage at R271 during prothrombin activation revealed by cryo-EM.Blood · 2026Article
- Molecular mechanisms of protease precursor autoprocessing of RNA viruses: a comprehensive review.Virology journal · 2026Review
- Identifying and controlling inactive and active conformations of a serine protease.Science advances · 2025Article
- Nonallosteric activation of posttranslational modification enzymes by active site-directed inhibitors.Computational and structural biotechnology journal · 2024Article
- Cryo-EM structures of coagulation factors.Research and practice in thrombosis and haemostasis · 2022Review
- Article
- The active site region plays a critical role in NaThe Journal of biological chemistry · 2022Article
- Proteolytic activity of contact factor zymogens.Journal of thrombosis and haemostasis : JTH · 2021Review
- Mechanisms of ligand binding.Biophysics reviews · 2020Review
- Zymogen and activated protein C have similar structural architecture.The Journal of biological chemistry · 2020Article
- Article
- Protease activity in single-chain prekallikrein.Blood · 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
- Thrombin Exosite Maturation and Ligand Binding at ABE II Help Stabilize PAR-Binding Competent Conformation at ABE I.Biochemistry · 2019Article
- Structural Biology and Protein Engineering of Thrombolytics.Computational and structural biotechnology journal · 2019Review
- Enhancing the anticoagulant profile of meizothrombin.Biomolecular concepts · 2018Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Trypsin-like proteases are synthesized as zymogens and activated through a mechanism that folds the active site for efficient binding and catalysis. Ligand binding to the active site is therefore a valuable source of information on the changes that accompany zymogen activation. Using the physiologically relevant transition of the clotting zymogen prothrombin to the mature protease thrombin, we show that the mechanism of ligand recognition follows selection within a pre-existing ensemble of conformations with the active site accessible (E) or inaccessible (E*) to binding. Prothrombin exists mainly in the E* conformational ensemble and conversion to thrombin produces two dominant changes: a progressive shift toward the E conformational ensemble triggered by removal of the auxiliary domains upon cleavage at R271 and a drastic drop of the rate of ligand dissociation from the active site triggered by cleavage at R320. Together, these effects produce a significant (700-fold) increase in binding affinity. Limited proteolysis reveals how the E*-E equilibrium shifts during prothrombin activation and influences exposure of the sites of cleavage at R271 and R320. These new findings on the molecular underpinnings of prothrombin activation are relevant to other zymogens with modular assembly involved in blood coagulation, complement and fibrinolysis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.