ArticlePLoS computational biology2017
Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil.
Article in PLoS computational biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 26 citations in OpenAlex.
- Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility.The Journal of physiology · 2025Article
- Review
- Dynamics of the Pre-Powerstroke Myosin Lever Arm and the Effects of Omecamtiv Mecarbil.International journal of molecular sciences · 2024Article
- Myosin Isoform-Dependent Effect of Omecamtiv Mecarbil on the Regulation of Force Generation in Human Cardiac Muscle.International journal of molecular sciences · 2024Article
- Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction.Nature communications · 2024Article
- Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction.bioRxiv : the preprint server for biology · 2023Article
- Binding pocket dynamics along the recovery stroke of human β-cardiac myosin.PLoS computational biology · 2023Article
- Comparative study of binding pocket structure and dynamics in cardiac and skeletal myosin.Biophysical journal · 2023Article
- Myosin modulators: emerging approaches for the treatment of cardiomyopathies and heart failure.The Journal of clinical investigation · 2022Review
- The PyInteraph Workflow for the Study of Interaction Networks From Protein Structural Ensembles.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain.PLoS computational biology · 2020Article
- Conformational distributions of isolated myosin motor domains encode their mechanochemical properties.eLife · 2020Article
- Structure and functional analysis of the Legionella pneumophila chitinase ChiA reveals a novel mechanism of metal-dependent mucin degradation.PLoS pathogens · 2020Article
- Myocardial Contractility: Historical and Contemporary Considerations.Frontiers in physiology · 2020Article
- New therapies for the treatment of heart failure: a summary of recent accomplishments.Therapeutics and clinical risk management · 2019Review
- Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke.Nature communications · 2018Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear. We present here a Molecular Dynamics study of the motor domain of human cardiac myosin bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution. We found that OM has a double effect on myosin dynamics, inducing a) an increased coupling of the motions of the converter and lever arm subdomains to the rest of the protein and b) a rewiring of the network of dynamic correlations, which produces preferential communication pathways between the OM binding site and distant functional regions. The location of the residues responsible for these effects suggests possible strategies for the future development of improved drugs and the targeting of specific cardiomyopathy-related mutations.
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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.