A small molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle [Molecular Biophysics]

MYK-461 is a recently discovered novel small-molecule modulator of cardiac myosin that targets the underlying sarcomere hypercontractility of hypertrophic cardiomyopathy (HCM), one of the most prevalent heritable cardiovascular disorders. Studies on isolated cells and muscle fibers, as well as intact animals, have shown that MYK-461 inhibits sarcomere force production, thereby reducing cardiac function. Initial mechanistic studies have suggested that MYK-461 primarily reduces the steady-state ATPase activity by inhibiting the rate of phosphate release of β-cardiac myosin-S1, but the molecular mechanism of action of MYK-461 has not been described. Here we used steady-state and pre-steady-state kinetic analyses to investigate the mechanism of action of MYK-461. Transient kinetic analyses revealed that MYK-461 modulates multiple steps of the myosin chemomechanical cycle. In addition to decreasing the rate-limiting step of the cycle (phosphate release), MYK-461 reduced the number of myosin-S1 heads that can interact with the actin thin filament during transition from the weakly to the strongly bound state without affecting the intrinsic rate. MYK-461 also decreased the rate of myosin binding to actin in the ADP-bound state and the ADP-release rate from myosin-S1 alone. We therefore conclude that MYK-461 acts on multiple stages of the myosin chemomechanical cycle. While the primary mechanism of MYK-461 mediated inhibition of cardiac myosin is the decrease of phosphate release from β-cardiac myosin-S1, a secondary mechanism decreases the number of actin-binding heads transitioning from the weakly to the strongly bound state, which occurs prior to phosphate release, and may provide an additional method to modulate myosin function.

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