Molecular Structures Reveal Synergistic Rescue of Δ508 CFTR by Trikafta Modulators

TLDR: Cryo-electron microscopy structures of Δ508 CFTR in the absence and presence of CFTR modulators are presented to illustrate how the different modulators in Trikafta synergistically rescue Δ508CFTR structure and function.

Abstract: 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. Description How three drugs restore function Cystic fibrosis is caused by defects in a chloride channel crucial for proper fluid balance and secretion. Deletion of a single amino acid, phenylalanine 508 (Δ508), is the most common mutation and leads to misfolding and degradation of the protein before it can reach cell surfaces. Fiedorczuk and Chen determined the structures of the Δ508 channel bound to three drugs that are given in combination therapy to correct folding and potentiate the channel. They uncovered a binding site for one of the drugs, a dual function corrector and potentiator, that was not previously known. The structures showed only a partial correction of folding when only one corrector was provided, but full correction was achieved when type I and III correctors were bound. —MAF Molecular structures reveal how three drugs rectify the effects of the most common CFTR mutant in cystic fibrosis.