Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil.
Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil.
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DOI：
10.1038/s41467-017-00176-5
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发表时间：
2017-08-04
影响因子：
16.6
通讯作者：
Houdusse A
中科院分区：
文献类型：
--
作者：
Planelles-Herrero VJ;Hartman JJ;Robert-Paganin J;Malik FI;Houdusse A
Omecamtiv mecarbil是一种心脏肌球蛋白的选择性小分子激活剂，正在被开发用于射血分数降低的心力衰竭的潜在治疗。在此，我们确定了心脏肌球蛋白在动力冲程前状态下的晶体结构，这是动力学研究表明的最相关状态，分别测定了结合（2.45 Å）和未结合（3.10 Å）omecamtiv mecarbil的情况。Omecamtiv mecarbil既不改变运动机制，也不影响肌球蛋白结构。相反，omecamtiv mecarbil结合到一个变构位点，该位点将杠杆臂稳定在预备位置，导致心脏收缩开始前心脏肌球蛋白在预备状态下积累，从而增加了在心动周期开始时能够结合到肌动蛋白丝并进行动力冲程的头部数量。Omecamtiv mecarbil的作用机制也为揭示分子马达如何产生力提供了见解。
Omecamtiv mecarbil（OM）是一种心脏肌球蛋白激活剂，目前正处于心力衰竭治疗的临床试验阶段。在此，作者深入了解了其作用模式，并展示了结合到牛心脏肌球蛋白上的OM的晶体结构，这表明OM稳定了肌球蛋白的动力冲程前状态。
Omecamtiv mecarbil is a selective, small-molecule activator of cardiac myosin that is being developed as a potential treatment for heart failure with reduced ejection fraction. Here we determine the crystal structure of cardiac myosin in the pre-powerstroke state, the most relevant state suggested by kinetic studies, both with (2.45 Å) and without (3.10 Å) omecamtiv mecarbil bound. Omecamtiv mecarbil does not change the motor mechanism nor does it influence myosin structure. Instead, omecamtiv mecarbil binds to an allosteric site that stabilizes the lever arm in a primed position resulting in accumulation of cardiac myosin in the primed state prior to onset of cardiac contraction, thus increasing the number of heads that can bind to the actin filament and undergo a powerstroke once the cardiac cycle starts. The mechanism of action of omecamtiv mecarbil also provides insights into uncovering how force is generated by molecular motors. Omecamtiv mecarbil (OM) is a cardiac myosin activator that is currently in clinical trials for heart failure treatment. Here, the authors give insights into its mode of action and present the crystal structure of OM bound to bovine cardiac myosin, which shows that OM stabilizes the pre-powerstroke state of myosin.
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DOI：
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发表时间：
2009-10-01
影响因子：
2.2
作者：
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发表时间：
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影响因子：
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