ArticleJournal of molecular and cellular cardiology2010
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.
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 23 papers.
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Who cites it
23 citing papers in PubMed, 37 citations in OpenAlex.
- 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
- Conversion of a Cardiac Muscle Modulator from an Inhibitor to an Activator.ACS medicinal chemistry letters · 2023Article
- Fluorescence lifetime-based assay reports structural changes in cardiac muscle mediated by effectors of contractile regulation.The Journal of general physiology · 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
- A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue.Journal of molecular and cellular cardiology plus · 2022Article
- A Potent Fluorescent Reversible-Covalent Inhibitor of Cardiac Muscle Contraction.ACS medicinal chemistry letters · 2021Article
- Structural Changes beyond the EF-Hand Contribute to Apparent Calcium Binding Affinities: Insights from Parvalbumins.The journal of physical chemistry. B · 2021Article
- Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium.The Journal of clinical investigation · 2021Article
- Sarcomere integrated biosensor detects myofilament-activating ligands in real time during twitch contractions in live cardiac muscle.Journal of molecular and cellular cardiology · 2020Article
- Discovery of Novel Small-Molecule Calcium Sensitizers for Cardiac Troponin C: A Combined Virtual and Experimental Screening Approach.Journal of chemical information and modeling · 2020Article
- Mechanism of Cardiac Troponin C Calcium Sensitivity Modulation by Small Molecules Illuminated by Umbrella Sampling Simulations.Journal of chemical information and modeling · 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
- 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
- Probing the mechanism of cardiovascular drugs using a covalent levosimendan analog.Journal of molecular and cellular cardiology · 2016Article
- Review
- Targeting the sarcomere to correct muscle function.Nature reviews. Drug discovery · 2015Review
- Muscle dysfunction in hypertrophic cardiomyopathy: what is needed to move to translation?Journal of muscle research and cell motility · 2014Review
- Two structural motifs within canonical EF-hand calcium-binding domains identify five different classes of calcium buffers and sensors.PloS one · 2014Article
- Molecular basis of calcium-sensitizing and desensitizing mutations of the human cardiac troponin C regulatory domain: a multi-scale simulation study.PLoS computational biology · 2012Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The solution structure of Ca(2+)-bound regulatory domain of cardiac troponin C (cNTnC) in complex with the switch region of troponin I (cTnI(147-163)) and the calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfinamide (W7), has been determined by NMR spectroscopy. The structure reveals that the W7 naphthalene ring interacts with the terminal methyl groups of M47, M60, and M81 as well as aliphatic and aromatic side chains of several other residues in the hydrophobic pocket of cNTnC. The H3 ring proton of W7 also contacts the methyl groups of I148 and M153 of cTnI(147-163). The N-(6-aminohexyl) tail interacts primarily with the methyl groups of V64 and M81, which are located on the C- and D-helices of cNTnC. Compared to the structure of the cNTnC*Ca(2+)*W7 complex (Hoffman, R. M. B. and Sykes, B. D. (2009) Biochemistry 48, 5541-5552), the tail of W7 reorients slightly toward the surface of cNTnC while the ring remains in the hydrophobic pocket. The positively charged -NH(3)(+) group from the tail of W7 repels the positively charged R147 of cTnI(147-163). As a result, the N-terminus of the peptide moves away from cNTnC and the helical content of cTnI(147-163) is diminished, when compared to the structure of cNTnC*Ca(2+)*cTnI(147-163) (Li, M. X., Spyracopoulos, L., and Sykes B. D. (1999) Biochemistry 38, 8289-8298). Thus the ternary structure cNTnC*Ca(2+)*W7*cTnI(147-163) reported in this study offers an explanation for the approximately 13-fold affinity reduction of cTnI(147-163) for cNTnC*Ca(2+) in the presence of W7 and provides a structural basis for the inhibitory effect of W7 in cardiac muscle contraction. This generates molecular insight into structural features that are useful for the design of cTnC-specific Ca(2+)-desensitizing drugs.
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