Comparative study of binding pocket structure and dynamics in cardiac and skeletal myosin.
Comparative study of binding pocket structure and dynamics in cardiac and skeletal myosin.
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DOI：
10.1016/j.bpj.2022.11.2942
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发表时间：
2023-01-03
影响因子：
3.4
通讯作者：
Fornili, Arianna
中科院分区：
文献类型：
--
作者：
Antonovic, Anna Katarina;Ochala, Julien;Fornili, Arianna
近年来，由于小分子肌球蛋白调节剂可能用于心脏和骨骼肌病的治疗，其发展得到了越来越多的努力。Omecamtiv mecarbil （OM）是首个进入临床试验的同类心肌减肥药。它对慢速/ β -心肌肌球蛋白的选择性是其功能的核心；然而，与其他密切相关的亚型如快速型骨骼肌球蛋白相比，对这种亚型的选择性的潜在原因知之甚少。在这项工作中，我们比较了心肌和fasttype IIa骨骼肌球蛋白中OM结合位点的结构和动力学，以确定OM选择性的可能原因。我们发现骨骼肌蛋白中不同形状、大小和组成的结合袋直接影响OM的结合模式和相关亲和力，这可能是相互作用较弱和最佳分子识别较差的结果。此外，我们发现了OM结合位点附近的侧袋，与心脏异构体相比，骨骼肌球蛋白的可及性增加。这些发现可能为骨骼选择性化合物的开发铺平道路，这些化合物可以靶向蛋白质的这一区域，并有可能用于治疗先天性肌病，其中肌肉无力与肌球蛋白功能丧失有关。
The development of small molecule myosin modulators has seen an increased effort in recent years due to their possible use in the treatment of cardiac and skeletal myopathies. Omecamtiv mecarbil (OM) is the first-in-class cardiac myotrope and the first to enter clinical trials. Its selectivity toward slow/beta-cardiac myosin lies at the heart of its function; however, little is known about the underlying reasons for selectivity to this isoform as opposed to other closely related ones such as fast-type skeletal myosins. In this work, we compared the structure and dynamics of the OM binding site in cardiac and in fasttype IIa skeletal myosin to identify possible reasons for OM selectivity. We found that the different shape, size, and composition of the binding pocket in skeletal myosin directly affects the binding mode and related affinity of OM, which is potentially a result of weaker interactions and less optimal molecular recognition. Moreover, we identified a side pocket adjacent to the OM binding site that shows increased accessibility in skeletal myosin compared with the cardiac isoform. These findings could pave the way to the development of skeletal-selective compounds that can target this region of the protein and potentially be used to treat congenital myopathies where muscle weakness is related to myosin loss of function.
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影响因子：
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作者：
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通讯作者：
Shaw DE
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通讯作者：
Málnási-Csizmadia A