ArticleThe Journal of biological chemistry2014
Conformational activation of antithrombin by heparin involves an altered exosite interaction with protease.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 46 citations in OpenAlex.
- Analysis of the Phenotype and Gene Mutations of Two Families With Combined Mutations of Anticoagulant Protein Genes.Molecular genetics & genomic medicine · 2026Article
- Genetic and clinical characterization of two families with severe venous thromboembolism due to nonsense mutations in the SERPINC1 gene.Thrombosis journal · 2025Article
- The Effects of Heparin Binding and Arg596 Mutations on the Conformation of Thrombin-Antithrombin Michaelis Complex, Revealed by Enhanced Sampling Molecular Dynamics Simulations.International journal of molecular sciences · 2025Article
- The Allosteric Communication Network in the Activation of Antithrombin by Heparin.International journal of molecular sciences · 2025Article
- Interactions of proteins with heparan sulfate.Essays in biochemistry · 2024Review
- Identification of two point mutations associated with inherited antithrombin deficiency.Thrombosis journal · 2024Article
- Molecular Mechanisms of the Impaired Heparin Pentasaccharide Interactions in 10 Antithrombin Heparin Binding Site Mutants Revealed by Enhanced Sampling Molecular Dynamics.Biomolecules · 2024Article
- The Interaction of Factor Xa and IXa with Non-Activated Antithrombin in Michaelis Complex: Insights from Enhanced-Sampling Molecular Dynamics Simulations.Biomolecules · 2023Article
- Identification and characterization of two SERPINC1 mutations causing congenital antithrombin deficiency.Thrombosis journal · 2023Article
- Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis.Frontiers in cardiovascular medicine · 2022Review
- Cost-effectiveness of Argatroban Versus Heparin Anticoagulation in Adult Extracorporeal Membrane Oxygenation Patients.Hospital pharmacy · 2021Article
- Paramount Importance of Core Conformational Changes for Heparin Allosteric Activation of Antithrombin.Biochemistry · 2021Article
- N-Glycosylation as a Tool to Study Antithrombin Secretion, Conformation, and Function.International journal of molecular sciences · 2021Article
- Anticoagulant and signaling functions of antithrombin.Journal of thrombosis and haemostasis : JTH · 2020Review
- Analysis of protein missense alterations by combining sequence- and structure-based methods.Molecular genetics & genomic medicine · 2020Article
- Approaches to prevent bleeding associated with anticoagulants: current status and recent developments.Drug delivery and translational research · 2018Review
- Cooperative Interactions of Three Hotspot Heparin Binding Residues Are Critical for Allosteric Activation of Antithrombin by Heparin.Biochemistry · 2018Article
- Recurrent mutations in aOncotarget · 2017Article
- A novel antithrombin domain dictates the journey's end of a proteinase.The Journal of biological chemistry · 2017Article
- Disease-causing mutations in the serpin antithrombin reveal a key domain critical for inhibiting protease activities.The Journal of biological chemistry · 2017Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Heparin allosterically activates antithrombin as an inhibitor of factors Xa and IXa by enhancing the initial Michaelis complex interaction of inhibitor with protease through exosites. Here, we investigate the mechanism of this enhancement by analyzing the effects of alanine mutations of six putative antithrombin exosite residues and three complementary protease exosite residues on antithrombin reactivity with these proteases in unactivated and heparin-activated states. Mutations of antithrombin Tyr(253) and His(319) exosite residues produced massive 10-200-fold losses in reactivity with factors Xa and IXa in both unactivated and heparin-activated states, indicating that these residues made critical attractive interactions with protease independent of heparin activation. By contrast, mutations of Asn(233), Arg(235), Glu(237), and Glu(255) exosite residues showed that these residues made both repulsive and attractive interactions with protease that depended on the activation state and whether the critical Tyr(253)/His(319) residues were mutated. Mutation of factor Xa Arg(143), Lys(148), and Arg(150) residues that interact with the exosite in the x-ray structure of the Michaelis complex confirmed the importance of all residues for heparin-activated antithrombin reactivity and Arg(150) for native serpin reactivity. These results demonstrate that the exosite is a key determinant of antithrombin reactivity with factors Xa and IXa in the native as well as the heparin-activated state and support a new model of allosteric activation we recently proposed in which a balance between attractive and repulsive exosite interactions in the native state is shifted to favor the attractive interactions in the activated state through core conformational changes induced by heparin binding.
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