Timing of CFTR Pore Opening and Structure of Its Transition State

Ben Sorum, Dávid Czégé, László Csanády

Research output: Contribution to journalArticle

31 Citations (Scopus)


In CFTR, the chloride ion channel mutated in cystic fibrosis (CF) patients, pore opening is coupled to ATP-binding-induced dimerization of two cytosolic nucleotide binding domains (NBDs) and closure to dimer disruption following ATP hydrolysis. CFTR opening rate, unusually slow because of its high-energy transition state, is further slowed by CF mutation ΔF508. Here, we exploit equilibrium gating of hydrolysis-deficient CFTR mutant D1370N and apply rate-equilibrium free-energy relationship analysis to estimate relative timing of opening movements in distinct protein regions. We find clear directionality of motion along the longitudinal protein axis and identify an opening transition-state structure with the NBD dimer formed but the pore still closed. Thus, strain at the NBD/pore-domain interface, the ΔF508 mutation locus, underlies the energetic barrier for opening. Our findings suggest a therapeutic opportunity to stabilize this transition-state structure pharmacologically in ΔF508-CFTR to correct its opening defect, an essential step toward restoring CFTR function.

Original languageEnglish
Pages (from-to)724-733
Number of pages10
Issue number3
Publication statusPublished - Oct 22 2015


ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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