ArticleBiochemistry2008
Defining the binding site of levosimendan and its analogues in a regulatory cardiac troponin C-troponin I complex.
Article in Biochemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 37 citations in OpenAlex.
- Advancing drug development for atrial fibrillation by prioritising findings from human genetic association studies.EBioMedicine · 2024Article
- Cardiac Troponin ActivatorJournal of medicinal chemistry · 2024Article
- 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
- 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
- The Coadministration of Levosimendan and Exenatide Offers a Significant Cardioprotective Effect to Isolated Rat Hearts against Ischemia/Reperfusion Injury.Journal of cardiovascular development and disease · 2022Article
- Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing.ACS medicinal chemistry letters · 2019Article
- Biophysical Derangements in Genetic Cardiomyopathies.Heart failure clinics · 2018Review
- New Insights in Cardiac Calcium Handling and Excitation-Contraction Coupling.Advances in experimental medicine and biology · 2018Review
- Structures reveal details of small molecule binding to cardiac troponin.Journal of molecular and cellular cardiology · 2016Review
- Fluorescence Based Characterization of Calcium Sensitizer Action on the Troponin Complex.Chemical biology & drug design · 2016Article
- Cardiac Troponin and Tropomyosin: Structural and Cellular Perspectives to Unveil the Hypertrophic Cardiomyopathy Phenotype.Frontiers in physiology · 2016Review
- Targeting the sarcomere to correct muscle function.Nature reviews. Drug discovery · 2015Review
- Inhibition of phosphodiesterase-3 by levosimendan is sufficient to account for its inotropic effect in failing human heart.British journal of pharmacology · 2014Article
- Crystal structure of cardiac troponin C regulatory domain in complex with cadmium and deoxycholic acid reveals novel conformation.Journal of molecular biology · 2011Article
- HD exchange and PLIMSTEX determine the affinities and order of binding of Ca2+ with troponin C.Biochemistry · 2011Article
- A structural and functional perspective into the mechanism of Ca2+-sensitizers that target the cardiac troponin complex.Journal of molecular and cellular cardiology · 2010Article
- Solution structure of the regulatory domain of human cardiac troponin C in complex with the switch region of cardiac troponin I and W7: the basis of W7 as an inhibitor of cardiac muscle contraction.Journal of molecular and cellular cardiology · 2010Article
- Calcium sensitisation impairs diastolic relaxation in post-ischaemic myocardium: implications for the use of Ca(2+) sensitising inotropes after cardiac surgery.European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery · 2010Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The interaction of Cardiac Troponin C (cTnC) and Cardiac Troponin I (cTnI) plays a critical role in transmitting the Ca (2+) signal to the other myofilament proteins in the activation of cardiac muscle contraction. As such, the cTnC-cTnI interface is a logical target for cardiotonic agents such as levosimendan that can modulate the Ca (2+) sensitivity of the myofilaments. Evidence indicates that drug candidates may exert their effects by targeting a site formed by binding of the switch region of cTnI to the regulatory N domain of cTnC (cNTnC). In this study, we utilized two-dimensional (1)H- (15)N HSQC NMR spectroscopy to monitor the binding of levosimendan and its analogues, CMDP, AMDP, CI-930, imazodan, and MPDP, to cNTnC.Ca (2+) in complex with two versions of the switch region of cTnI (cTnI 147-163 and cTnI 144-163). Levosimendan, CMDP, AMDP, and CI-930 were found to bind to both cNTnC.Ca (2+).cTnI 147-163 and cNTnC.Ca (2+).cTnI 144-163 complexes. These compounds contain a methyl group that is absent in MPDP or imazodan. Thus, the methyl group is one of the pharmacophores responsible for the action of these pyridazinone drugs on cTnC. Furthermore, the results showed that the cNTnC.Ca (2+).cTnI 144-163 complex presents a higher-affinity binding site for these compounds than the cNTnC.Ca (2+).cTnI 147-163 complex. This is consistent with our observation that the affinity of cTnI 144-163 for cNTnC.Ca (2+) is approximately 10-fold stronger than that of cTnI 147-163, likely a result of electrostatic forces between the N-terminal RRV extension in cTnI 144-163 and the acidic residues in the C and D helices of cNTnC. These results will help in the delineation of the mode of action of levosimendan on the important functional unit of cardiac troponin that constitutes the regulatory domain of cTnC and the switch region of cTnI.
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