ArticleProceedings of the National Academy of Sciences of the United States of America2019
Cardiac myosin activation with 2-deoxy-ATP via increased electrostatic interactions with actin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 46 citations in OpenAlex.
- Probing relaxed myosin states in hypertrophic cardiomyopathy by second harmonic-generation microscopy.eLife · 2026Article
- Cellular and molecular contractile function in aged human skeletal muscle is altered by phosphate and acidosis and partially reversed with an ATP analog.American journal of physiology. Cell physiology · 2025Article
- Thick-Filament-Based Regulation and the Determinants of Force Generation.Biomedicines · 2025Article
- Interacting myosin head dynamics and their modification by 2'-deoxy-ADP.Biophysical journal · 2024Article
- Mechanisms of a novel regulatory light chain-dependent cardiac myosin inhibitor.The Journal of general physiology · 2024Article
- Multiscale modeling shows how 2'-deoxy-ATP rescues ventricular function in heart failure.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The biochemically defined super relaxed state of myosin-A paradox.The Journal of biological chemistry · 2024Article
- Mitochondrial transplantation ameliorates doxorubicin-induced cardiac dysfunction via activating glutamine metabolism.iScience · 2023Article
- The structural and functional integrities of porcine myocardium are mostly preserved by cryopreservation.The Journal of general physiology · 2023Article
- Danicamtiv Increases Myosin Recruitment and Alters Cross-Bridge Cycling in Cardiac Muscle.Circulation research · 2023Article
- Machine learning meets Monte Carlo methods for models of muscle's molecular machinery to classify mutations.The Journal of general physiology · 2023Article
- Integrating comparative modeling and accelerated simulations reveals conformational and energetic basis of actomyosin force generation.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.Journal of molecular and cellular cardiology · 2023Article
- Structural OFF/ON transitions of myosin in relaxed porcine myocardium predict calcium-activated force.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling.Quarterly reviews of biophysics · 2023Review
- Reduced cardiac muscle power with low ATP simulating heart failure.Biophysical journal · 2022Article
- Small Angle X-ray Diffraction as a Tool for Structural Characterization of Muscle Disease.International journal of molecular sciences · 2022Review
- Subcellular Remodeling in Filamin C Deficient Mouse Hearts Impairs Myocyte Tension Development during Progression of Dilated Cardiomyopathy.International journal of molecular sciences · 2022Article
- Cardiac myosin contraction and mechanotransduction in health and disease.The Journal of biological chemistry · 2021Review
- Translational research on Myology and Mobility Medicine: 2021 semi-virtual PDM3 from Thermae of Euganean Hills, May 26 - 29, 2021.European journal of translational myology · 2021Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
The naturally occurring nucleotide 2-deoxy-adenosine 5'-triphosphate (dATP) can be used by cardiac muscle as an alternative energy substrate for myosin chemomechanical activity. We and others have previously shown that dATP increases contractile force in normal hearts and models of depressed systolic function, but the structural basis of these effects has remained unresolved. In this work, we combine multiple techniques to provide structural and functional information at the angstrom-nanometer and millisecond time scales, demonstrating the ability to make both structural measurements and quantitative kinetic estimates of weak actin-myosin interactions that underpin sarcomere dynamics. Exploiting dATP as a molecular probe, we assess how small changes in myosin structure translate to electrostatic-based changes in sarcomere function to augment contractility in cardiac muscle. Through Brownian dynamics simulation and computational structural analysis, we found that deoxy-hydrolysis products [2-deoxy-adenosine 5'-diphosphate (dADP) and inorganic phosphate (Pi)] bound to prepowerstroke myosin induce an allosteric restructuring of the actin-binding surface on myosin to increase the rate of cross-bridge formation. We then show experimentally that this predicted effect translates into increased electrostatic interactions between actin and cardiac myosin in vitro. Finally, using small-angle X-ray diffraction analysis of sarcomere structure, we demonstrate that the proposed increased electrostatic affinity of myosin for actin causes a disruption of the resting conformation of myosin motors, resulting in their repositioning toward the thin filament before activation. The dATP-mediated structural alterations in myosin reported here may provide insight into an improved criterion for the design or selection of small molecules to be developed as therapeutic agents to treat systolic dysfunction.
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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.