Cystic fibrosis (CF) is one of the most common progressive, lethal genetic diseases among the Caucasian population. This disease is caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is widely expressed on the surface of epithelial cells, where it transports chloride ions to the extracellular space. Despite the protein being present at the membrane, certain mutations impair channel gating, reducing chloride ion transport. To address the gating defect, a type of CFTR modulator called “potentiator” has been developed to increase the ion flux of mutant CFTR by prolonging the opening of the channel. Currently, there are two potentiators, ivacaftor (VX-770) and GLPG1837, which have been captured in high-resolution cryo-EM structures bound to CFTR in conformations with some open-state features, showing that both occupy the same transmembrane binding site. However, the molecular mechanisms by which these potentiators modulate CFTR channel dynamics remain poorly understood, particularly in membrane environments resembling the epithelial cell membrane. In this study, we use molecular dynamics simulation to investigate how ivacaftor and GLPG1837 influence ion translocation through CFTR. This framework can reveal molecular motions characteristic of the open state that are reinforced by potentiator binding. Insights from this study can serve as a guideline to develop future therapeutics with improved pharmacological properties to maximally rescue mutant CFTR.
Ho et al. (2026) studied this question.