ArticleProceedings of the National Academy of Sciences of the United States of America2010
NMR resonance assignments of thrombin reveal the conformational and dynamic effects of ligation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 92 citations in OpenAlex.
- Identifying and controlling inactive and active conformations of a serine protease.Science advances · 2025Article
- The Prothrombin-Prothrombinase Interaction.Sub-cellular biochemistry · 2024Review
- From haemadin to haemanorm: Synthesis and characterization of full-length haemadin from the leech Haemadipsa sylvestris and of a novel bivalent, highly potent thrombin inhibitor (haemanorm).Protein science : a publication of the Protein Society · 2023Article
- Dynamic allostery in thrombin-a review.Frontiers in molecular biosciences · 2023Review
- A systematic approach for evaluating the role of surface-exposed loops in trypsin-like serine proteases applied to the 170 loop in coagulation factor VIIa.Scientific reports · 2022Article
- Serine protease dynamics revealed by NMR analysis of the thrombin-thrombomodulin complex.Scientific reports · 2021Article
- 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
- Residues W215, E217 and E192 control the allosteric E*-E equilibrium of thrombin.Scientific reports · 2019Article
- Allostery in Coagulation Factor VIIa Revealed by Ensemble Refinement of Crystallographic Structures.Biophysical journal · 2019Article
- Thrombin Exosite Maturation and Ligand Binding at ABE II Help Stabilize PAR-Binding Competent Conformation at ABE I.Biochemistry · 2019Article
- 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
- Dynamic Consequences of Mutation of Tryptophan 215 in Thrombin.Biochemistry · 2018Article
- Interplay between conformational selection and zymogen activation.Scientific reports · 2018Article
- Deciphering Conformational Changes Associated with the Maturation of Thrombin Anion Binding Exosite I.Biochemistry · 2017Article
- Mechanistic insights into thrombin's switch between "slow" and "fast" forms.Physical chemistry chemical physics : PCCP · 2017Article
- Non-canonical proteolytic activation of human prothrombin by subtilisin fromThe Journal of biological chemistry · 2017Article
- Single-chain factor XII: a new form of activated factor XII.Current opinion in hematology · 2017Review
7 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
The serine protease thrombin is generated from its zymogen prothrombin at the end of the coagulation cascade. Thrombin functions as the effector enzyme of blood clotting by cleaving several procoagulant targets, but also plays a key role in attenuating the hemostatic response by activating protein C. These activities all depend on the engagement of exosites on thrombin, either through direct interaction with a substrate, as with fibrinogen, or by binding to cofactors such as thrombomodulin. How thrombin specificity is controlled is of central importance to understanding normal hemostasis and how dysregulation causes bleeding or thrombosis. The binding of ligands to thrombin via exosite I and the coordination of Na(+) have been associated with changes in thrombin conformation and activity. This phenomenon has become known as thrombin allostery, although direct evidence of conformational change, identification of the regions involved, and the functional consequences remain unclear. Here we investigate the conformational and dynamic effects of thrombin ligation at the active site, exosite I and the Na(+)-binding site in solution, using modern multidimensional NMR techniques. We obtained full resonance assignments for thrombin in seven differently liganded states, including fully unliganded apo thrombin, and have created a detailed map of residues that change environment, conformation, or dynamic state in response to each relevant single or multiple ligation event. These studies reveal that apo thrombin exists in a highly dynamic zymogen-like state, and relies on ligation to achieve a fully active conformation. Conformational plasticity confers upon thrombin the ability to be at once selective and promiscuous.
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Registered trials
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.