ArticleBiochemistry2011
Crystallographic and kinetic evidence of allostery in a trypsin-like protease.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed.
- Dynamic allostery in thrombin-a review.Frontiers in molecular biosciences · 2023Review
- Structure-mechanics statistical learning uncovers mechanical relay in proteins.Chemical science · 2022Article
- How Thrombomodulin Enables W215A/E217A Thrombin to Cleave Protein C but Not Fibrinogen.Biochemistry · 2022Article
- The active site region plays a critical role in NaThe Journal of biological chemistry · 2022Article
- Article
- Role of the activation peptide in the mechanism of protein C activation.Scientific reports · 2020Article
- Article
- Sodium-induced population shift drives activation of thrombin.Scientific reports · 2020Article
- Review
- Membrane interactions of intrinsically disordered proteins: The example of alpha-synuclein.Biochimica et biophysica acta. Proteins and proteomics · 2019Review
- Residues W215, E217 and E192 control the allosteric E*-E equilibrium of thrombin.Scientific reports · 2019Article
- Dynamic Consequences of Mutation of Tryptophan 215 in Thrombin.Biochemistry · 2018Article
- 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
- Discovery of a novel conformational equilibrium in urokinase-type plasminogen activator.Scientific reports · 2017Article
- Induced Fit Is a Special Case of Conformational Selection.Biochemistry · 2017Article
- NMR reveals a dynamic allosteric pathway in thrombin.Scientific reports · 2017Article
- Loop Electrostatics Asymmetry Modulates the Preexisting Conformational Equilibrium in Thrombin.Biochemistry · 2016Article
- Discrimination between conformational selection and induced fit protein-ligand binding using Integrated Global Fit analysis.European biophysics journal : EBJ · 2016Article
- Molecular Basis of Enhanced Activity in Factor VIIa-Trypsin Variants Conveys Insights into Tissue Factor-mediated Allosteric Regulation of Factor VIIa Activity.The Journal of biological chemistry · 2016Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Protein allostery is based on the existence of multiple conformations in equilibrium linked to distinct functional properties. Although evidence of allosteric transitions is relatively easy to identify by functional studies, structural detection of a pre-existing equilibrium between alternative conformations remains challenging even for textbook examples of allosteric proteins. Kinetic studies show that the trypsin-like protease thrombin exists in equilibrium between two conformations where the active site is either collapsed (E*) or accessible to substrate (E). However, structural demonstration that the two conformations exist in the same enzyme construct free of ligands has remained elusive. Here we report the crystal structure of the thrombin mutant N143P in the E form, which complements the recently reported structure in the E* form, and both the E and E* forms of the thrombin mutant Y225P. The side chain of W215 moves 10.9 Å between the two forms, causing a displacement of 6.6 Å of the entire 215-217 segment into the active site that in turn opens or closes access to the primary specificity pocket. Rapid kinetic measurements of p-aminobenzamidine binding to the active site confirm the existence of the E*-E equilibrium in solution for wild-type and the mutants N143P and Y225P. These findings provide unequivocal proof of the allosteric nature of thrombin and lend strong support to the recent proposal that the E*-E equilibrium is a key property of the trypsin fold.
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