PDF(Pubmed)
Abstract：
Curcumin, a major constituent of turmeric (Curcuma longa L.), has beneficial effects against several diseases. In cystic fibrosis (CF), this compound improves patients\' symptoms by recovering the activity of a number of mutants of the cystic fibrosis transmembrane conductance regulator (CFTR). Despite holding promise in the treatment of CF, the curcumin binding site in CFTR and the molecular mechanism of activation of this channel are still unknown. The results of this study, based on docking and molecular dynamics (MD) simulations, allow us to propose that curcumin binds the closed ATP-free CFTR near the nucleotide-binding domain 1 (NBD1)/ICl1/ICl4 interface. The bound ligand, once approached by the nucleotide-binding domain 2 (NBD2) during transient channel opening, lays at a multiple interdomain cross point. Thereafter, curcumin can bridge NBD1 and NBD2, and also ICL1/ICL4 and ICL2/ICL3, finally tightening the same interdomain interactions that normally uphold the open conformation in the wild-type ATP-bound CFTR. The proposed binding site is compatible with biochemical observations made in previous CFTR-curcumin interaction studies. These findings provide a framework for the design of novel drugs that activate CFTR mutants characterized by defects in ATP binding and/or NBD dimerization or even lacking NBD2.
摘要：
姜黄素,姜黄（姜黄）的主要成分，对几种疾病有有益的影响。在囊性纤维化（CF）中，该化合物通过恢复囊性纤维化跨膜传导调节因子(CFTR)的多种突变体的活性来改善患者的症状.尽管在治疗CF方面有希望，CFTR中姜黄素的结合位点及其激活该通道的分子机制尚不清楚。这项研究的结果，基于对接和分子动力学(MD)模拟，允许我们提出姜黄素结合核苷酸结合域1（NBD1）/ICl1/ICl4界面附近的封闭的无ATPCFTR。结合的配体，一旦在瞬时通道开放期间被核苷酸结合域2（NBD2）接近，位于多个域间交叉点。此后,姜黄素可以桥接NBD1和NBD2，以及ICL1/ICL4和ICL2/ICL3，最终收紧通常在野生型ATP结合的CFTR中保持开放构象的相同域间相互作用。所提出的结合位点与先前的CFTR-姜黄素相互作用研究中的生化观察结果相容。这些发现为设计新型药物提供了框架,所述新型药物激活以ATP结合和/或NBD二聚化缺陷或甚至缺乏NBD2为特征的CFTR突变体。
