ArticleBiophysical chemistry2011
Rigidification of the autolysis loop enhances Na(+) binding to thrombin.
Article in Biophysical chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Possible Thrombus-clearing Mechanism and Modification Suggestion of β-sitosterol.Current drug targets · 2026Article
- Nanoclay/Polymer-Based Hydrogels and Enzyme-Loaded Nanostructures for Wound Healing Applications.Gels (Basel, Switzerland) · 2021Review
- Article
- Review
- Molecular dynamics simulations of aptamer-binding reveal generalized allostery in thrombin.Journal of biomolecular structure & dynamics · 2017Article
- Loop Electrostatics Asymmetry Modulates the Preexisting Conformational Equilibrium in Thrombin.Biochemistry · 2016Article
- Article
- Kinetic dissection of the pre-existing conformational equilibrium in the trypsin fold.The Journal of biological chemistry · 2015Article
- Isothermal titration calorimetry of ion-coupled membrane transporters.Methods (San Diego, Calif.) · 2015Article
- Trypsinogen activation as observed in accelerated molecular dynamics simulations.Protein science : a publication of the Protein Society · 2014Article
- Binding thermodynamics of a glutamate transporter homolog.Nature structural & molecular biology · 2013Article
- Conformational selection in trypsin-like proteases.Current opinion in structural biology · 2012Review
- Conformational selection or induced fit? A critical appraisal of the kinetic mechanism.Biochemistry · 2012Article
- Crystal structures of prethrombin-2 reveal alternative conformations under identical solution conditions and the mechanism of zymogen activation.Biochemistry · 2011Article
- Allostery in trypsin-like proteases suggests new therapeutic strategies.Trends in biotechnology · 2011Review
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5 authors.
Funding
Abstract
Binding of Na(+) to thrombin ensures high activity toward physiological substrates and optimizes the procoagulant and prothrombotic roles of the enzyme in vivo. Under physiological conditions of pH and temperature, the binding affinity of Na(+) is weak due to large heat capacity and enthalpy changes associated with binding, and the K(d)=80 mM ensures only 64% saturation of the site at the concentration of Na(+) in the blood (140 mM). Residues controlling Na(+) binding and activation have been identified. Yet, attempts to improve the interaction of Na(+) with thrombin and possibly increase catalytic activity under physiological conditions have so far been unsuccessful. Here we report how replacement of the flexible autolysis loop of human thrombin with the homologous rigid domain of the murine enzyme results in a drastic (up to 10-fold) increase in Na(+) affinity and a significant improvement in the catalytic activity of the enzyme. Rigidification of the autolysis loop abolishes the heat capacity change associated with Na(+) binding observed in the wild-type and also increases the stability of thrombin. These findings have general relevance to protein engineering studies of clotting proteases and trypsin-like enzymes.
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