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Abstract：
Mavacamten, formerly known as MYK-461 is a recently discovered novel small-molecule modulator of cardiac myosin that targets the underlying sarcomere hypercontractility of hypertrophic cardiomyopathy, one of the most prevalent heritable cardiovascular disorders. Studies on isolated cells and muscle fibers as well as intact animals have shown that mavacamten inhibits sarcomere force production, thereby reducing cardiac contractility. Initial mechanistic studies have suggested that mavacamten 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 mavacamten has not been described. Here we used steady-state and presteady-state kinetic analyses to investigate the mechanism of action of mavacamten. Transient kinetic analyses revealed that mavacamten modulates multiple steps of the myosin chemomechanical cycle. In addition to decreasing the rate-limiting step of the cycle (phosphate release), mavacamten 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. Mavacamten 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 mavacamten acts on multiple stages of the myosin chemomechanical cycle. Although the primary mechanism of mavacamten-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 before phosphate release and may provide an additional method to modulate myosin function.
摘要：
Mavacamten,以前被称为MYK-461是最近发现的一种新的心肌肌球蛋白小分子调节剂，靶向肥厚型心肌病潜在的肌节过度收缩，最普遍的遗传性心血管疾病之一。对分离的细胞和肌纤维以及完整动物的研究表明，mavacamten抑制肌节力的产生，从而降低心脏收缩力。最初的机理研究表明，mavacamten主要通过抑制β-心肌肌球蛋白S1的磷酸盐释放速率来降低稳态ATPase活性，但尚未描述mavacamten的分子作用机制。在这里，我们使用稳态和预稳态动力学分析来研究mavacampen的作用机理。瞬态动力学分析显示，mavacamten调节肌球蛋白化学机械循环的多个步骤。除了减少循环的限速步骤（磷酸盐释放）之外，mavacamten减少了从弱结合状态过渡到强结合状态期间可以与肌动蛋白细丝相互作用的肌球蛋白S1头部的数量，而不会影响固有速率。Mavacamten还降低了肌球蛋白在ADP结合状态下与肌动蛋白结合的速率以及单独的肌球蛋白S1的ADP释放速率。我们,因此,得出的结论是，mavacten作用于肌球蛋白化学机械周期的多个阶段。尽管mavacamten介导的抑制心肌肌球蛋白的主要机制是减少β-心肌肌球蛋白S1的磷酸盐释放，但次要机制减少了从弱结合状态过渡到强结合状态的肌动蛋白结合头的数量，这发生在磷酸盐释放之前，并且可以提供调节肌球蛋白功能的另一种方法。
