Sorbonne Université, Muséum National d'Histoire Naturelle, UMR CNRS 7590, IRD, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, 75005, Paris, France.
Iktos, Paris, France.
Cell Mol Life Sci. 2018 Oct;75(20):3829-3855. doi: 10.1007/s00018-018-2835-7. Epub 2018 May 19.
Cryo-electron microscopy (cryo-EM) has recently provided invaluable experimental data about the full-length cystic fibrosis transmembrane conductance regulator (CFTR) 3D structure. However, this experimental information deals with inactive states of the channel, either in an apo, quiescent conformation, in which nucleotide-binding domains (NBDs) are widely separated or in an ATP-bound, yet closed conformation. Here, we show that 3D structure models of the open and closed forms of the channel, now further supported by metadynamics simulations and by comparison with the cryo-EM data, could be used to gain some insights into critical features of the conformational transition toward active CFTR forms. These critical elements lie within membrane-spanning domains but also within NBD1 and the N-terminal extension, in which conformational plasticity is predicted to occur to help the interaction with filamin, one of the CFTR cellular partners.
冷冻电镜（cryo-EM）最近提供了关于全长囊性纤维化跨膜电导调节剂（CFTR）3D 结构的宝贵实验数据。然而，这些实验信息涉及通道的非活性状态，要么处于apo 状态，即核苷酸结合域（NBD）广泛分离的静止构象，要么处于结合 ATP 但关闭的构象。在这里，我们表明，现在通过元动力学模拟和与 cryo-EM 数据的比较进一步支持的通道开放和关闭形式的 3D 结构模型，可用于深入了解朝向活跃 CFTR 形式的构象转变的关键特征。这些关键要素位于跨膜结构域内，但也位于 NBD1 和 N 端延伸内，预计构象灵活性将发生以帮助与 CFTR 细胞伴侣之一的细丝蛋白相互作用。
