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TitleCFTR function, pathology and pharmacology at single-molecule resolution.
Journal, issue, pagesNature, Vol. 616, Issue 7957, Page 606-614, Year 2023
Publish dateMar 22, 2023
AuthorsJesper Levring / Daniel S Terry / Zeliha Kilic / Gabriel Fitzgerald / Scott C Blanchard / Jue Chen /
PubMed AbstractThe cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates salt and fluid homeostasis across epithelial membranes. Alterations in CFTR cause cystic fibrosis, a ...The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates salt and fluid homeostasis across epithelial membranes. Alterations in CFTR cause cystic fibrosis, a fatal disease without a cure. Electrophysiological properties of CFTR have been analysed for decades. 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.
External linksNature / PubMed:36949202 / PubMed Central
MethodsEM (single particle)
Resolution4.3 Å
Structure data

29637

8fzq

EMDB-29637, PDB-8fzq:
Dehosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
Method: EM (single particle) / Resolution: 4.3 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Ion Channel

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