ArticleProceedings of the National Academy of Sciences of the United States of America2016
Atomic resolution probe for allostery in the regulatory thin filament.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 59 citations in OpenAlex.
- Implications of S-glutathionylation of sarcomere proteins in cardiac disorders, therapies, and diagnosis.Frontiers in cardiovascular medicine · 2022Pooled it
- Resolving the structure and dynamics of the disordered C terminus of human cardiac troponin T and effects of cardiomyopathic mutations.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models.The Journal of clinical investigation · 2025Article
- The transmission of mutation effects in a multiprotein machine: A comprehensive metadynamics study of the cardiac thin filament.Protein science : a publication of the Protein Society · 2024Article
- Arg92Leu-cTnT Alters the cTnC-cTnI Interface Disrupting PKA-Mediated Relaxation.Circulation research · 2024Article
- Umbrella Sampling Simulations of Cardiac Thin Filament Reveal Thermodynamic Consequences of Troponin I Inhibitory Peptide Mutations.Journal of chemical information and modeling · 2023Article
- Structure and Dynamics of the Flexible Cardiac Troponin T Linker Domain in a Fully Reconstituted Thin Filament.Biochemistry · 2022Article
- Computational and biophysical determination of pathogenicity of variants of unknown significance in cardiac thin filament.JCI insight · 2021Article
- Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation.The Journal of general physiology · 2021Article
- A troponin T variant linked with pediatric dilated cardiomyopathy reduces the coupling of thin filament activation to myosin and calcium binding.Molecular biology of the cell · 2021Article
- Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation.The Journal of general physiology · 2021Article
- Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy.Chemical science · 2021Article
- A Proposed Mechanism for the Initial Myosin Binding Event on the Cardiac Thin Filament: A Metadynamics Study.The journal of physical chemistry letters · 2021Article
- Complexity in genetic cardiomyopathies and new approaches for mechanism-based precision medicine.The Journal of general physiology · 2021Article
- Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts.JCI insight · 2020Article
- Protein-Protein Docking Reveals Dynamic Interactions of Tropomyosin on Actin Filaments.Biophysical journal · 2020Article
- Strategies for targeting the cardiac sarcomere: avenues for novel drug discovery.Expert opinion on drug discovery · 2020Review
- Variant R94C inJournal of the American Heart Association · 2020Article
- Troponin structure and function: a view of recent progress.Journal of muscle research and cell motility · 2020Review
- Docking Troponin T onto the Tropomyosin Overlapping Domain of Thin Filaments.Biophysical journal · 2020Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Calcium binding and dissociation within the cardiac thin filament (CTF) is a fundamental regulator of normal contraction and relaxation. Although the disruption of this complex, allosterically mediated process has long been implicated in human disease, the precise atomic-level mechanisms remain opaque, greatly hampering the development of novel targeted therapies. To address this question, we used a fully atomistic CTF model to test both Ca(2+) binding strength and the energy required to remove Ca(2+) from the N-lobe binding site in WT and mutant troponin complexes that have been linked to genetic cardiomyopathies. This computational approach is combined with measurements of in vitro Ca(2+) dissociation rates in fully reconstituted WT and cardiac troponin T R92L and R92W thin filaments. These human disease mutations represent known substitutions at the same residue, reside at a significant distance from the calcium binding site in cardiac troponin C, and do not affect either the binding pocket affinity or EF-hand structure of the binding domain. Both have been shown to have significantly different effects on cardiac function in vivo. We now show that these mutations independently alter the interaction between the Ca(2+) ion and cardiac troponin I subunit. This interaction is a previously unidentified mechanism, in which mutations in one protein of a complex indirectly affect a third via structural and dynamic changes in a second to yield a pathogenic change in thin filament function that results in mutation-specific disease states. We can now provide atom-level insight that is potentially highly actionable in drug design.
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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.