Structural identification of a hotspot on CFTR for potentiation

Abstract

Keeping the gate open Cystic fibrosis is a progressive disease that affects lung function and is often fatal. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). One class of mutants impairs ion conductance, and the drug ivacaftor acts by increasing the ion flux. Liu et al. describe high-resolution structures of CFTR bound to ivacaftor and to an investigational drug GLPG1837 that also potentiates ion flow. The two drugs bind at the same site in the transmembrane region. This site coincides with a hinge involved in channel gating, suggesting that the drugs may stabilize the open conformation of the channel. Science , this issue p. 1184