Planelles-Herrero Vicente J, Hartman James J, Robert-Paganin Julien, Malik Fady I, Houdusse Anne
Structural Motility, Institut Curie, PSL Research University, CNRS, UMR 144, F-75005, Paris, France.
Sorbonne Universités, UPMC Univ Paris06, Sorbonne Universités, IFD, 4 Place Jussieu, 75252, Paris, cedex 05, France.
Nat Commun. 2017 Aug 4;8(1):190. doi: 10.1038/s41467-017-00176-5.
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.
奥米卡替麦卡比是一种选择性小分子心肌肌球蛋白激活剂，正作为射血分数降低的心力衰竭的潜在治疗药物进行研发。在此，我们确定了处于动力冲程前状态的心肌肌球蛋白的晶体结构，这是动力学研究表明的最相关状态，分别为结合奥米卡替麦卡比（2.45 Å）和未结合奥米卡替麦卡比（3.10 Å）的情况。奥米卡替麦卡比不会改变运动机制，也不会影响肌球蛋白结构。相反，奥米卡替麦卡比结合到一个变构位点，该位点将杠杆臂稳定在启动位置，导致心肌肌球蛋白在心脏收缩开始前处于启动状态积累，从而增加了一旦心动周期开始就能结合到肌动蛋白丝并经历动力冲程的头部数量。奥米卡替麦卡比的作用机制也为揭示分子马达如何产生力提供了见解。奥米卡替麦卡比（OM）是一种心肌肌球蛋白激活剂，目前正处于治疗心力衰竭的临床试验阶段。在此，作者深入探讨了其作用模式，并展示了与牛心肌肌球蛋白结合的OM的晶体结构，该结构表明OM稳定了肌球蛋白的动力冲程前状态。
