Timing of CFTR Pore Opening and Structure of Its Transition State
  • Metaadatok
Tartalom: http://real.mtak.hu/30312/
Archívum: MTA Könyvtár
Gyűjtemény: Status = Published


Type = Article
Cím:
Timing of CFTR Pore Opening and Structure of Its Transition State
Létrehozó:
Sorum, Em Ben
Czégé, Dávid
Csanády, László
Dátum:
2015
Téma:
QH3011 Biochemistry / biokémia
R1 Medicine (General) / orvostudomány általában
Tartalmi leírás:
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 DeltaF508. 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 DeltaF508 mutation locus, underlies the energetic barrier for opening. Our findings suggest a therapeutic opportunity to stabilize this transition-state structure pharmacologically in DeltaF508-CFTR to correct its opening defect, an essential step toward restoring CFTR function.
Nyelv:
angol
Típus:
Article
PeerReviewed
info:eu-repo/semantics/article
Formátum:
text
Azonosító:
Sorum, Em Ben and Czégé, Dávid and Csanády, László (2015) Timing of CFTR Pore Opening and Structure of Its Transition State. CELL, 163 (3). pp. 724-733. ISSN 0092-8674
Kapcsolat:
MTMT:2964742; doi:10.1016/j.cell.2015.09.052