ArticleProtein science : a publication of the Protein Society2017
Molecular mechanisms underlying deoxy-ADP.Pi activation of pre-powerstroke myosin.
Article in Protein science : a publication of the Protein Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- Interacting myosin head dynamics and their modification by 2'-deoxy-ADP.Biophysical journal · 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
- 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
- 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
- Modulation of post-powerstroke dynamics in myosin II by 2'-deoxy-ADP.Archives of biochemistry and biophysics · 2021Article
- Cardiac myosin activation with 2-deoxy-ATP via increased electrostatic interactions with actin.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- A mixed-kinetic model describes unloaded velocities of smooth, skeletal, and cardiac muscle myosin filaments in vitro.Science advances · 2017Article
- Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil.PLoS computational biology · 2017Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Myosin activation is a viable approach to treat systolic heart failure. We previously demonstrated that striated muscle myosin is a promiscuous ATPase that can use most nucleoside triphosphates as energy substrates for contraction. When 2-deoxy ATP (dATP) is used, it acts as a myosin activator, enhancing cross-bridge binding and cycling. In vivo, we have demonstrated that elevated dATP levels increase basal cardiac function and rescues function of infarcted rodent and pig hearts. Here we investigate the molecular mechanism underlying this physiological effect. We show with molecular dynamics simulations that the binding of dADP.Pi (dATP hydrolysis products) to myosin alters the structure and dynamics of the nucleotide binding pocket, myosin cleft conformation, and actin binding sites, which collectively yield a myosin conformation that we predict favors weak, electrostatic binding to actin. In vitro motility assays at high ionic strength were conducted to test this prediction and we found that dATP increased motility. These results highlight alterations to myosin that enhance cross-bridge formation and reveal a potential mechanism that may underlie dATP-induced improvements in cardiac function.
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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.