ArticleThe Journal of biological chemistry2015
Kinetic dissection of the pre-existing conformational equilibrium in the trypsin fold.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 33 citations in OpenAlex.
- Review
- Low molecular weight ligands bind to CYP3A4 via a branched induced fit mechanism: Implications for OArchives of biochemistry and biophysics · 2023Article
- Comparative sequence analysis of vitamin K-dependent coagulation factors.Journal of thrombosis and haemostasis : JTH · 2022Article
- The active site region plays a critical role in NaThe Journal of biological chemistry · 2022Article
- Probing activation-driven changes in coagulation factor IX by mass spectrometry.Journal of thrombosis and haemostasis : JTH · 2021Article
- Article
- Mechanisms of ligand binding.Biophysics reviews · 2020Review
- Role of the activation peptide in the mechanism of protein C activation.Scientific reports · 2020Article
- Article
- Protease activity in single-chain prekallikrein.Blood · 2020Article
- 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
- Review
- 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
- Metal-cation regulation of enzyme dynamics is a key factor influencing the activity of S-adenosyl-L-homocysteine hydrolase from Pseudomonas aeruginosa.Scientific reports · 2018Article
- Interplay between conformational selection and zymogen activation.Scientific reports · 2018Article
- Non-canonical proteolytic activation of human prothrombin by subtilisin fromThe Journal of biological chemistry · 2017Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Structural biology has recently documented the conformational plasticity of the trypsin fold for both the protease and zymogen in terms of a pre-existing equilibrium between closed (E*) and open (E) forms of the active site region. How such plasticity is manifested in solution and affects ligand recognition by the protease and zymogen is poorly understood in quantitative terms. Here we dissect the E*-E equilibrium with stopped-flow kinetics in the presence of excess ligand or macromolecule. Using the clotting protease thrombin and its zymogen precursor prethrombin-2 as relevant models we resolve the relative distribution of the E* and E forms and the underlying kinetic rates for their interconversion. In the case of thrombin, the E* and E forms are distributed in a 1:4 ratio and interconvert on a time scale of 45 ms. In the case of prethrombin-2, the equilibrium is shifted strongly (10:1 ratio) in favor of the closed E* form and unfolds over a faster time scale of 4.5 ms. The distribution of E* and E forms observed for thrombin and prethrombin-2 indicates that zymogen activation is linked to a significant shift in the pre-existing equilibrium between closed and open conformations that facilitates ligand binding to the active site. These findings broaden our mechanistic understanding of how conformational transitions control ligand recognition by thrombin and its zymogen precursor prethrombin-2 and have direct relevance to other members of the trypsin fold.
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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.