ArticleJournal of molecular and cellular cardiology2010
A structural and functional perspective into the mechanism of Ca2+-sensitizers that target the cardiac troponin complex.
Article in Journal of molecular and cellular cardiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 66 citations in OpenAlex.
- Trial
- Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscles and Structure-Activity Relationship.Journal of chemical information and modeling · 2023Article
- Umbrella Sampling Simulations of Cardiac Thin Filament Reveal Thermodynamic Consequences of Troponin I Inhibitory Peptide Mutations.Journal of chemical information and modeling · 2023Article
- Conversion of a Cardiac Muscle Modulator from an Inhibitor to an Activator.ACS medicinal chemistry letters · 2023Article
- Discovery of novel cardiac troponin activators using fluorescence polarization-based high throughput screening assays.Scientific reports · 2023Article
- Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscle and Structure Activity Relationship.bioRxiv : the preprint server for biology · 2023Article
- Study on influencing factors of anthracycline-induced subclinical cardiotoxicity in DLBCL patients administered (R)-CHOP.BMC cancer · 2022Observational
- Small Molecule RPI-194 Stabilizes Activated Troponin to Increase the Calcium Sensitivity of Striated Muscle Contraction.Frontiers in physiology · 2022Article
- A Potent Fluorescent Reversible-Covalent Inhibitor of Cardiac Muscle Contraction.ACS medicinal chemistry letters · 2021Article
- Molecular dynamics provides new insights into the mechanism of calcium signal transduction and interdomain interactions in cardiac troponin.FEBS open bio · 2021Article
- Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.Journal of cardiovascular pharmacology · 2020Review
- Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use.Cardiac failure review · 2020Review
- Optimizing fluorine labelling forJournal of biomolecular NMR · 2020Article
- Mechanism of Cardiac Troponin C Calcium Sensitivity Modulation by Small Molecules Illuminated by Umbrella Sampling Simulations.Journal of chemical information and modeling · 2019Article
- Thioimidate Bond Formation between Cardiac Troponin C and Nitrile-containing Compounds.ACS medicinal chemistry letters · 2019Article
- Small molecule studies: the fourth wave of muscle research.Journal of muscle research and cell motility · 2019Article
- Article
- Successful Identification of Cardiac Troponin Calcium Sensitizers Using a Combination of Virtual Screening and ROC Analysis of Known Troponin C Binders.Journal of chemical information and modeling · 2017Article
- Molecular Effects of cTnC DCM Mutations on Calcium Sensitivity and Myofilament Activation-An Integrated Multiscale Modeling Study.The journal of physical chemistry. B · 2016Article
- Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca2+-sensitive myofilaments.American journal of physiology. Heart and circulatory physiology · 2016Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
The Ca(2+) dependent interaction between troponin I (cTnI) and troponin C (cTnC) triggers contraction in heart muscle. Heart failure is characterized by a decrease in cardiac output, and compounds that increase the sensitivity of cardiac muscle to Ca(2+) have therapeutic potential. The Ca(2+)-sensitizer, levosimendan, targets cTnC; however, detailed understanding of its mechanism has been obscured by its instability. In order to understand how this class of positive inotropes function, we investigated the mode of action of two fluorine containing novel analogs of levosimendan; 2',4'-difluoro(1,1'-biphenyl)-4-yloxy acetic acid (dfbp-o) and 2',4'-difluoro(1,1'-biphenyl)-4-yl acetic acid (dfbp). The affinities of dfbp and dfbp-o for the regulatory domain of cTnC were measured in the absence and presence of cTnI by NMR spectroscopy, and dfbp-o was found to bind more strongly than dfbp. Dfbp-o also increased the affinity of cTnI for cTnC. Dfbp-o increased the Ca(2+)-sensitivity of demembranated cardiac trabeculae in a manner similar to levosimendan. The high resolution NMR solution structure of the cTnC-cTnI-dfbp-o ternary complex showed that dfbp-o bound at the hydrophobic interface formed by cTnC and cTnI making critical interactions with residues such as Arg147 of cTnI. In the absence of cTnI, docking localized dfbp-o to the same position in the hydrophobic groove of cTnC. The structural and functional data reveal that the levosimendan class of Ca(2+)-sensitizers work by binding to the regulatory domain of cTnC and stabilizing the pivotal cTnC-cTnI regulatory unit via a network of hydrophobic and electrostatic interactions, in contrast to the destabilizing effects of antagonists such as W7 at the same interface.
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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.