Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan.
School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Curr Opin Pharmacol. 2017 Jun;34:98-104. doi: 10.1016/j.coph.2017.09.015. Epub 2017 Nov 5.
One major breakthrough in cystic fibrosis research in the past decade is the development of drugs that target the root cause of the disease-dysfunctional CFTR protein. One of the compounds, Ivacaftor or Kalydeco, which has been approved for clinical use since 2012, acts by promoting the gating function of CFTR. Our recent studies have led to a gating model that features energetic coupling between nucleotide-binding domain (NBD) dimerization and gate opening/closing in CFTR's transmembrane domains (TMDs). Based on this model, we showed that ATP analogs can enhance CFTR gating by facilitating NBD dimerization, whereas Ivacaftor works by stabilizing the open channel conformation of the TMDs. This latter idea also explains the near omnipotence of Ivacaftor. Furthermore, this model identifies multiple approaches to synergistically boost the open probability of CFTR by influencing distinct molecular events that control gating conformational changes.
过去十年中，囊性纤维化研究的一个主要突破是开发了针对疾病根本原因——功能失调的 CFTR 蛋白的药物。其中一种化合物 Ivacaftor（也称为 Kalydeco）自 2012 年以来已被批准用于临床，其作用是促进 CFTR 的门控功能。我们最近的研究提出了一个门控模型，该模型的特征是核苷酸结合域（NBD）二聚化和 CFTR 跨膜域（TMD）的门打开/关闭之间的能量偶联。基于该模型，我们表明 ATP 类似物可以通过促进 NBD 二聚化来增强 CFTR 的门控，而 Ivacaftor 通过稳定 TMD 的开放通道构象起作用。后一种想法也解释了 Ivacaftor 的近乎全能性。此外，该模型确定了多种方法来通过影响控制门控构象变化的不同分子事件来协同提高 CFTR 的开放概率。
