Center for Biological Resources and Informatics, Tokyo Institute of Technology, 4259-B-62, Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
J Phys Chem B. 2013 Jan 10;117(1):83-93. doi: 10.1021/jp308315w. Epub 2012 Dec 19.
Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel belonging to the ATP binding cassette (ABC) protein superfamily. Currently, it remains unclear how ATP binding causes the opening of the channel gate at the molecular level. To clarify this mechanism, we first constructed an atomic model of the inward-facing CFTR using the X-ray structures of other ABC proteins. Molecular dynamics (MD) simulations were then performed to explore the structure and dynamics of the inward-facing CFTR in a membrane environment. In the MgATP-bound state, two nucleotide-binding domains (NBDs) formed a head-to-tail type of dimer, in which the ATP molecules were sandwiched between the Walker A and signature motifs. Alternatively, one of the final MD structures in the apo state was similar to that of a "closed-apo" conformation found in the X-ray analysis of ATP-free MsbA. Principal component analysis for the MD trajectory indicated that NBD dimerization causes significant structural and dynamical changes in the transmembrane domains (TMDs), which is likely indicative of the formation of a chloride ion access path. This study suggests that the free energy gain from ATP binding acts as a driving force not only for NBD dimerization but also for NBD-TMD concerted motions.
囊性纤维化跨膜电导调节因子 (CFTR) 是一种氯离子通道，属于 ATP 结合盒 (ABC) 蛋白超家族。目前，尚不清楚 ATP 结合如何在分子水平上引起通道门的打开。为了阐明这一机制，我们首先使用其他 ABC 蛋白的 X 射线结构构建了内向构象 CFTR 的原子模型。然后进行分子动力学 (MD) 模拟，以研究膜环境中内向构象 CFTR 的结构和动力学。在 MgATP 结合状态下，两个核苷酸结合域 (NBD) 形成头对头型二聚体，其中 ATP 分子夹在 Walker A 和特征基序之间。或者，apo 状态下的最后一个 MD 结构之一类似于无 ATP 的 MsbA 的 X 射线分析中发现的“关闭-apo”构象。MD 轨迹的主成分分析表明，NBD 二聚化导致跨膜结构域 (TMD) 发生显著的结构和动力学变化，这可能表明形成了氯离子进入途径。这项研究表明，来自 ATP 结合的自由能增益不仅是 NBD 二聚化的驱动力，也是 NBD-TMD 协同运动的驱动力。
