Neutraceuticals silybin B, resveratrol and epigallocatechin-3 gallate (EGCG) bind to troponin to restore the loss of lusitropy caused by cardiomyopathy mutations in vitro, in vivo, and in silico
Yang, Z.; Sheehan, A.; Messer, A.; Tsui, S.; Sparrow, A.; Redwood, C.; Kren, V.; Gould, I.; Marston, S.
Show abstract
Adrenergic activation of protein kinase A (PKA) targets the thin filaments of the cardiac muscle, specifically phosphorylating cTroponin I Ser22 and Ser23, causing a higher rate of Ca2+ dissociation from cTnC leading to a faster relaxation rate (lusitropy). This modulation is often suppressed by mutations that cause cardiomyopathy (uncoupling) and this could be sufficient to induce cardiomyopathy. A drug that could restore the phosphorylation-dependent modulation of relaxation rate could have the potential for treatment of these pathologies. We found, using single thin filament in vitro motility assays that the small molecules including silybin B, resveratrol, and epigallocatechin-3 gallate (EGCG) can restore coupling. We performed molecular dynamics simulations of the unphosphorylated and phosphorylated cardiac Troponin core with the TNNC1 G159D mutation. We found that silybin B, EGCG, and resveratrol restored the phosphorylation-induced change in the TnC helix A/B angle and the interdomain angle to wild-type values, whilst silybin A and epicatechin gallate (ECG) did not. In unphosphorylated G159D the recoupling molecules were observed to be frequently intercalated between The N terminal peptide of Troponin I and troponin C. In contrast, the controls, silybin A, and ECG bound to the surface. All of the interactions were diminished when troponin I was phosphorylated. We also performed studies with intact transgenic ACTC E99K mouse cells and TNNT2 R92Q-transfected guinea pig cardiomyocytes. The mutations blunt the increase in relaxation speed due to dobutamine; resveratrol, EGCG, and silybin B could restore the dobutamine response whilst silybin A did not. Thus recoupling by small molecules is demonstrated in vitro, in vivo, and in silico.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and non-ischemic human hearts 95%
- Human hypertrophic cardiomyopathy mutation R712L suppresses the working stroke of cardiac myosin and can be rescued by omecamtiv mecarbil 92%
- Inhibition of mutant RAS-RAF interaction by mimicking structural and dynamic properties of phosphorylated RAS 91%
Similar papers in this journal
- Molecular Mechanism of Regulation of RhoA GTPase by Phosphorylation of RhoGDI 91%
- Actin-binding compounds, discovered by FRET-based high-throughput screening, differentially affect skeletal and cardiac muscle 91%
- Ca2+ increases cardiac muscle viscoelasticity independent of active force development 91%
Similar papers in this journal
- Upgraded molecular models of the human KCNQ1 potassium channel 93%
- Toward in vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia 91%
- Ligand-induced Conformational Selection Predicts the Selectivity of Cysteine Protease Inhibitors 91%
Similar papers in this journal
- Multi-scale modeling shows that dielectric differences make NaV channels faster than KV channels 91%
- Tail Length and E525K Dilated Cardiomyopathy Mutant Alter Human β-Cardiac Myosin Super-Relaxed State 91%
- Mechanical dysfunction induced by a hypertrophic cardiomyopathy mutation is the primary driver of cellular adaptation 91%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.