Structural identification of a hotspot on CFTR for potentiation
Structural identification of a hotspot on CFTR for potentiation
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DOI：
10.1126/science.aaw7611
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发表时间：
2019-06-21
期刊：
影响因子：
56.9
通讯作者：
Chen, Jue
中科院分区：
文献类型：
--
作者：
Liu, Fangyu;Zhang, Zhe;Chen, Jue
囊性纤维化是由囊性纤维化跨膜传导调节因子（CFTR）突变引起的致命疾病。目前正在开发两大类药物：改善CFTR折叠的校正剂和恢复CFTR功能的增效剂。在这里，我们报告了两种与增效剂复合的人CFTR的冷冻电子显微镜结构：一种是美国食品和药物管理局（FDA）批准的3.3埃分辨率的药物ivacaftor，另一种是3.2埃分辨率的研究药物GLPG 1837。这两种药物，虽然化学性质不同，但结合到跨膜区域内的相同位点。突变表明，在这两种情况下，由蛋白质提供的氢键对于药物识别是重要的。ivacaftor和GLPG1837如何与CFTR相互作用的分子细节可能有助于治疗化合物的基于结构的优化。
Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve folding of CFTR and potentiators that recover the function of CFTR. Here, we report two cryo-electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA)-approved drug ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These two drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition. The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds.