Myosin II is the motor protein that enables muscle cells to contract and nonmuscle cells to move and change shape 1 . The molecule has two identical heads attached to an elongated tail, and can exist in two conformations: 10S and 6S, named for their sedimentation coefficients 2 , 3 . The 6S conformation has an extended tail and assembles into polymeric filaments, which pull on actin filaments to generate force and motion. In 10S myosin, the tail is folded into three segments and the heads bend back and interact with each other and the tail 3 – 7 , creating a compact conformation in which ATPase activity, actin activation and filament assembly are all highly inhibited 7 , 8 . This switched-off structure appears to function as a key energy-conserving storage molecule in muscle and nonmuscle cells 9 – 12 , which can be activated to form functional filaments as needed 13 —but the mechanism of its inhibition is not understood. Here we have solved the structure of smooth muscle 10S myosin by cryo-electron microscopy with sufficient resolution to enable improved understanding of the function of the head and tail regions of the molecule and of the key intramolecular contacts that cause inhibition. Our results suggest an atomic model for the off state of myosin II, for its activation and unfolding by phosphorylation, and for understanding the clustering of disease-causing mutations near sites of intramolecular interaction. High-resolution cryo-electron microscopy structure of smooth muscle myosin II in the inhibited state enables increased understanding of the functions of the head and tail regions in regulation of myosin activity and the pathological mechanisms of disease mutations.

中文翻译：

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肌球蛋白 II 的抑制型 (10S) 冷冻电镜结构


肌球蛋白 II 是一种运动蛋白，可使肌肉细胞收缩，并使非肌肉细胞移动和改变形状 1 。该分子有两个相同的头部连接到一个细长的尾部，并且可以以两种构象存在：10S 和 6S，以其沉降系数 2 、 3 命名。 6S 构象具有延伸的尾部并组装成聚合物丝，其拉动肌动蛋白丝以产生力和运动。在 10S 肌球蛋白中，尾部折叠成三段，头部向后弯曲并与彼此和尾部相互作用 3 – 7 ，形成紧凑的构象，其中 ATP 酶活性、肌动蛋白激活和丝组装均受到高度抑制 7 , 8 。这种关闭的结构似乎在肌肉和非肌肉细胞中充当关键的能量保存存储分子 9 – 12 ，可以根据需要被激活以形成功能性细丝 13 ，但其抑制机制尚不清楚。在这里，我们通过冷冻电子显微镜以足够的分辨率解析了平滑肌 10S 肌球蛋白的结构，以便更好地了解分子头部和尾部区域的功能以及引起抑制的关键分子内接触。我们的结果提出了肌球蛋白 II 关闭状态、通过磷酸化激活和展开以及了解分子内相互作用位点附近致病突变聚集的原子模型。抑制状态下平滑肌肌球蛋白 II 的高分辨率冷冻电子显微镜结构有助于加深对头尾区在调节肌球蛋白活性中的功能以及疾病突变的病理机制的了解。