Molecular models of the open and closed states of the whole human CFTR protein
Molecular models of the open and closed states of the whole human CFTR protein
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DOI：
10.1007/s00018-009-0133-0
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发表时间：
2009-11-01
影响因子：
8
通讯作者：
Callebaut, Isabelle
中科院分区：
文献类型：
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作者：
Mornon, Jean-Paul;Lehn, Pierre;Callebaut, Isabelle
囊性纤维化跨膜电导调节因子(CFTR)参与囊性纤维化(CF)，是一种属于三磷酸腺苷结合盒(ABC)超家族的氯离子通道。以Sav1866的实验结构为模板，我们先前模拟了人的CFTR结构，包括膜跨越结构域(MSD)和核苷酸结合结构域(NBD)，呈向外构象(开放通道状态)。在此，我们在MSBA最新修正结构的基础上构建了CFTR内向构象(闭合通道)的模型，并比较了这两种状态通道的结构特征。有趣的是，包括F508(Delta F508是最常见的CF突变)在内的MSD：NBD偶联接口基本保持不变。这一预测由调控R结构域的建模完成，得到了实验数据的支持，并为更好地理解CFTR的功能，特别是使CFTR成为ABC转运蛋白中唯一通道的结构特征提供了分子基础。
Cystic fibrosis transmembrane conductance regulator (CFTR), involved in cystic fibrosis (CF), is a chloride channel belonging to the ATP-binding cassette (ABC) superfamily. Using the experimental structure of Sav1866 as template, we previously modeled the human CFTR structure, including membrane-spanning domains (MSD) and nucleotide-binding domains (NBD), in an outward-facing conformation (open channel state). Here, we constructed a model of the CFTR inward-facing conformation (closed channel) on the basis of the recent corrected structures of MsbA and compared the structural features of those two states of the channel. Interestingly, the MSD:NBD coupling interfaces including F508 (Delta F508 being the most common CF mutation) are mainly left unchanged. This prediction, completed by the modeling of the regulatory R domain, is supported by experimental data and provides a molecular basis for a better understanding of the functioning of CFTR, especially of the structural features that make CFTR the unique channel among the ABC transporters.