Abstract
Myosin's lever arm undergoes structural changes that are coupled to its biochemical state during ATPase cycling in muscle. Structural states of myosin's lever can be detected directly using the high-precision, high-throughput technique of transient time-resolved FRET, (TR)2FRET, revealing kinetics, thermodynamics, and allosteric coupling. We have previously used this technique to investigate mechanochemical coupling in skeletal myosin and cardiac myosin perturbed by the heart failure drug omecamtiv mecarbil. Here we investigate other small molecule modulators of cardiac myosins mechanochemistry: arachidonic acid, EMD 57003, and compounds developed by MyoKardia, under investigation for treating hypertrophic cardiomyopathy. We find that one Myk compound dramatically decreases the amplitude of the fast phase of the power stroke, but does not significantly affect the rate of this transition. These data suggest that the compound shifts the equilibrium constant for hydrolysis toward the pre-hydrolysis state. This is in sharp contrast to the effect of omecamtiv mecarbil (Cytokinetics) under investigation for systolic heart failure, which shifts the equilibrium constant toward the post-hydrolysis states. This work was supported by NIH AR032961 & AR057220 (DDT), American Heart Association Scientist Development Grant (JMM), and Graduate Excellence Fellowship-University of MN (JAR).
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