Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil.
Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil.
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DOI：
10.1371/journal.pcbi.1005826
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发表时间：
2017-11
影响因子：
4.3
通讯作者：
Fornili A
中科院分区：
文献类型：
--
作者：
Hashem S;Tiberti M;Fornili A
骨骼肌和心肌疾病的药理学治疗的新的有希望的途径依赖于直接的肌节调节剂，其是可以直接结合到肌节蛋白并抑制或增强其活性的分子。最近的一项突破是发现了肌球蛋白激活剂Omecamtiv Mecarbil（OM），该药物已被证明可增加心肌的功率输出，目前正处于治疗心力衰竭的临床试验中。虽然OM对肌球蛋白的机械化学循环的总体作用是增加肌节中与肌动蛋白强烈结合的肌球蛋白分子的比例，但其作用的分子基础仍然不完全清楚。我们在这里提出了一个分子动力学研究的人心肌肌球蛋白的电机域绑定到OM，药物对蛋白质的动力学性质的影响进行了研究首次与原子分辨率。我们发现OM对肌球蛋白动力学具有双重作用，诱导a）转换器和杠杆臂亚结构域的运动与蛋白质其余部分的耦合增加，以及B）动态相关性网络的重新布线，这在OM结合位点和远距离功能区域之间产生优先通信途径。负责这些作用的残基的位置为未来开发改进的药物和靶向特定的心肌病相关突变提供了可能的策略。心肌肌球蛋白是一种负责心肌收缩的运动蛋白。目前正在通过使用肌球蛋白调节剂开发治疗心脏病的新策略，肌球蛋白调节剂是可以与肌球蛋白相互作用并改变其活性的小分子。与传统药物相比，这种方法的优势在于，通过直接靶向心脏肌球蛋白，可以减少药物的副作用。此外，一系列分子的可用性可以将肌球蛋白精细调节到所需的活性水平，这为开发更精确和个性化的药物治疗提供了可能性。在这项工作中，我们研究了最近发现的心肌肌球蛋白激活剂Omecamtiv Mecarbil，以了解其作用机制。特别是，我们使用分子动力学模拟来解开药物对肌球蛋白运动的影响，这与其功能密切相关。我们发现Omecamtiv对肌球蛋白动力学有很强的影响，它改变了蛋白质中对其功能至关重要的区域相互作用的方式。我们使用这些数据来识别与心脏病相关的基因突变，这些基因突变可以被药物靶向，并提出一种设计具有不同治疗特性的药物的可能途径。
New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear. We present here a Molecular Dynamics study of the motor domain of human cardiac myosin bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution. We found that OM has a double effect on myosin dynamics, inducing a) an increased coupling of the motions of the converter and lever arm subdomains to the rest of the protein and b) a rewiring of the network of dynamic correlations, which produces preferential communication pathways between the OM binding site and distant functional regions. The location of the residues responsible for these effects suggests possible strategies for the future development of improved drugs and the targeting of specific cardiomyopathy-related mutations. Cardiac myosin is a motor protein responsible for the contraction of the heart muscle. New strategies for the cure of heart diseases are currently being developed by using myosin modulators, which are small molecules that can interact with myosin and modify its activity. The advantage of this approach over traditional drugs is that by directly targeting cardiac myosin it is possible to have drugs with reduced side effects. Moreover, the availability of a spectrum of molecules to finely tune myosin to a desired level of activity opens the possibility to develop more precise and personalised drug therapies. In this work, we study a recently discovered activator of cardiac myosin, omecamtiv mecarbil, in order to understand its mechanism of action. In particular, we use Molecular Dynamics simulations to unravel the effects of the drug on myosin motions, which are closely related to its function. We find that omecamtiv has a strong effect on myosin dynamics and it changes the way regions of the protein that are critical for its function interact with each other. We use these data to identify genetic mutations associated with heart diseases that could be targeted by the drug and to suggest a possible route to design drugs with different therapeutic properties.
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影响因子：
3.7
作者：
Lindorff-Larsen K;Maragakis P;Piana S;Eastwood MP;Dror RO;Shaw DE
通讯作者：
Shaw DE
DOI：
10.1016/j.str.2010.01.014
发表时间：
2010-03-14
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Cecchini M;Alexeev Y;Karplus M
通讯作者：
Karplus M
影响因子：
2.9
作者：
Liu, Yingying;White, Howard D.;Forgacs, Eva
通讯作者：
Forgacs, Eva
DOI：
10.1073/pnas.0909636107
发表时间：
2010-03-16
影响因子：
11.1
作者：
Elber, Ron;West, Anthony
通讯作者：
West, Anthony
影响因子：
5.7
作者：
Koppole, Sampath;Smith, Jeremy C.;Fischer, Stefan
通讯作者：
Fischer, Stefan