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Publication Abstract from PubMed

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates salt and fluid homeostasis across epithelial membranes(1). Alterations in CFTR cause cystic fibrosis, a fatal disease without a cure(2,3). Electrophysiological properties of CFTR have been analysed for decades(4-6). The structure of CFTR, determined in two globally distinct conformations, underscores its evolutionary relationship with other ATP-binding cassette transporters. However, direct correlations between the essential functions of CFTR and extant structures are lacking at present. Here we combine ensemble functional measurements, single-molecule fluorescence resonance energy transfer, electrophysiology and kinetic simulations to show that the two nucleotide-binding domains (NBDs) of human CFTR dimerize before channel opening. CFTR exhibits an allosteric gating mechanism in which conformational changes within the NBD-dimerized channel, governed by ATP hydrolysis, regulate chloride conductance. The potentiators ivacaftor and GLPG1837 enhance channel activity by increasing pore opening while NBDs are dimerized. Disease-causing substitutions proximal (G551D) or distal (L927P) to the ATPase site both reduce the efficiency of NBD dimerization. These findings collectively enable the framing of a gating mechanism that informs on the search for more efficacious clinical therapies.

CFTR function, pathology and pharmacology at single-molecule resolution.,Levring J, Terry DS, Kilic Z, Fitzgerald G, Blanchard S, Chen J Nature. 2023 Mar 22. doi: 10.1038/s41586-023-05854-7. PMID:36949202^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.