Hwang et al. integrate new structural insights with prior functional studies to reveal the functional anatomy of CFTR chloride channels.

VX-770 is a potentiator of the CFTR channel and an approved therapy for cystic fibrosis. Yeh et al. find that the apparent affinity of a new potentiator, GLPG1837, is state dependent and propose an allosteric modulation model to explain the potency and efficacy of CFTR potentiators.

The permeant ion nitrate modulates CFTR gating to increase its open probability through a mechanism similar to that of VX-770.

Identification of the binding sites for small molecules that alleviate gating defects in CFTR would assist rational drug design for the treatment of cystic fibrosis. Yeh et al. identify two potential binding sites for prototypical CFTR potentiators at the interface of CFTR’s two transmembrane domains.

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