Molecular Structures Reveal Synergistic Rescue of Δ508 CFTR by Trikafta Modulators

The predominant mutation causing cystic fibrosis, the 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 a folding corrector tezacaftor (VX-661), a channel potentiator ivacaftor (VX-770), and a 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. Elexacaftor partially, when used alone, and fully, when combined with a type I corrector, rectified interdomain assembly defects in Δ508 CFTR. These data illustrate how the different modulators in Trikafta synergistically rescue Δ508 CFTR structure and function.