ArticleProceedings of the National Academy of Sciences of the United States of America2017
Heart failure drug changes the mechanoenzymology of the cardiac myosin powerstroke.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed.
- Knowledge mapping of targeted therapy for hypertrophic cardiomyopathy: A bibliometric analysis of myosin inhibitor research.Medicine · 2026Article
- A myosin hypertrophic cardiomyopathy mutation disrupts the super-relaxed state and boosts contractility by enhanced actin attachment.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Theoretical treatment of tension transients in muscle following sudden changes in orthophosphate concentration: implications for energy transduction.Journal of muscle research and cell motility · 2025Article
- A FRET assay to monitor different structural states of human β-cardiac myosin including the interacting-heads motif.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Modulation of striated-muscle contractility by a high-affinity myosin-targeting peptide.Biophysical journal · 2025Article
- Development of bifunctional fluorescent probes and their application to α-helix labelling.Organic & biomolecular chemistry · 2025Article
- Review
- A mechanokinetic actomyosin model predicts different orthophosphate sensitivities of force and ATP turnover rate during isometric muscle contraction.Frontiers in physiology · 2025Article
- Mechanistic insights into effects of the cardiac myosin activator omecamtiv mecarbil from mechanokinetic modelling.Frontiers in physiology · 2025Article
- A FRET assay to quantitate levels of the human β-cardiac myosin interacting heads motif based on its near-atomic resolution structure.bioRxiv : the preprint server for biology · 2024Article
- Probing actin-activated ATP turnover kinetics of human cardiac myosin II by single molecule fluorescence.Cytoskeleton (Hoboken, N.J.) · 2024Article
- Single-Molecule Investigation of Load-Dependent Actomyosin Dissociation Kinetics for Cardiac and Slow Skeletal Myosin.Small (Weinheim an der Bergstrasse, Germany) · 2024Article
- Myosin Isoform-Dependent Effect of Omecamtiv Mecarbil on the Regulation of Force Generation in Human Cardiac Muscle.International journal of molecular sciences · 2024Article
- Kinetics and mapping of Ca-driven calmodulin conformations on skeletal and cardiac muscle ryanodine receptors.Nature communications · 2024Article
- Harnessing molecular mechanism for precision medicine in dilated cardiomyopathy caused by a mutation in troponin T.bioRxiv : the preprint server for biology · 2024Article
- Missense mutations in the central domains of cardiac myosin binding protein-C and their potential contribution to hypertrophic cardiomyopathy.The Journal of biological chemistry · 2024Article
- Omecamtiv Mecarbil in the treatment of heart failure: the past, the present, and the future.Frontiers in cardiovascular medicine · 2024Review
- Cardiac myosin-binding protein C N-terminal interactions with myosin and actin filaments: Opposite effects of phosphorylation and M-domain mutations.Journal of molecular and cellular cardiology · 2024Article
- Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening.Nature communications · 2023Article
- Effect of the Novel Myotrope Danicamtiv on Cross-Bridge Behavior in Human Myocardium.Journal of the American Heart Association · 2023Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors.
Funding
Abstract
Omecamtiv mecarbil (OM), a putative heart failure therapeutic, increases cardiac contractility. We hypothesize that it does this by changing the structural kinetics of the myosin powerstroke. We tested this directly by performing transient time-resolved FRET on a ventricular cardiac myosin biosensor. Our results demonstrate that OM stabilizes myosin's prepowerstroke structural state, supporting previous measurements showing that the drug shifts the equilibrium constant for myosin-catalyzed ATP hydrolysis toward the posthydrolysis biochemical state. OM slowed the actin-induced powerstroke, despite a twofold increase in the rate constant for actin-activated phosphate release, the biochemical step in myosin's ATPase cycle associated with force generation and the conversion of chemical energy into mechanical work. We conclude that OM alters the energetics of cardiac myosin's mechanical cycle, causing the powerstroke to occur after myosin weakly binds to actin and releases phosphate. We discuss the physiological implications for these changes.
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