Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, NY 10065, USA.
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Science. 2022 Oct 21;378(6617):284-290. doi: 10.1126/science.ade2216. Epub 2022 Oct 20.
The predominant mutation causing cystic fibrosis, a deletion of phenylalanine 508 (Δ508) in the cystic fibrosis transmembrane conductance regulator (CFTR), leads to severe defects in CFTR biogenesis and function. The advanced therapy Trikafta combines the folding corrector tezacaftor (VX-661), the channel potentiator ivacaftor (VX-770), and the dual-function modulator elexacaftor (VX-445). However, it is unclear how elexacaftor exerts its effects, in part because the structure of Δ508 CFTR is unknown. Here, we present cryo-electron microscopy structures of Δ508 CFTR in the absence and presence of CFTR modulators. When used alone, elexacaftor partially rectified interdomain assembly defects in Δ508 CFTR, but when combined with a type I corrector, did so fully. These data illustrate how the different modulators in Trikafta synergistically rescue Δ508 CFTR structure and function.
导致囊性纤维化的主要突变是囊性纤维化跨膜电导调节因子（CFTR）中苯丙氨酸 508 的缺失（Δ508），这导致 CFTR 生物发生和功能的严重缺陷。Trikafta 是一种先进的治疗方法，它结合了折叠校正剂 tezacaftor（VX-661）、通道增强剂 ivacaftor（VX-770）和双功能调节剂 elexacaftor（VX-445）。然而，elexacaftor 如何发挥作用尚不清楚，部分原因是 Δ508 CFTR 的结构尚不清楚。在这里，我们展示了缺乏和存在 CFTR 调节剂时 Δ508 CFTR 的冷冻电子显微镜结构。单独使用时，elexacaftor 部分纠正了 Δ508 CFTR 中结构域间组装的缺陷，但与 I 型校正剂联合使用时则完全纠正了缺陷。这些数据说明了 Trikafta 中的不同调节剂如何协同拯救 Δ508 CFTR 的结构和功能。
