dc.contributor.author |
Sorum, Ben |
|
dc.contributor.author |
Czégé, Dávid |
|
dc.contributor.author |
Csanády, László |
|
dc.date.accessioned |
2016-10-20T11:05:53Z |
|
dc.date.available |
2016-10-20T11:05:53Z |
|
dc.date.issued |
2015 |
|
dc.identifier.citation |
pagination=724-733;
journalVolume=163;
journalIssueNumber=3;
journalTitle=CELL; |
|
dc.identifier.uri |
http://repo.lib.semmelweis.hu//handle/123456789/2505 |
|
dc.identifier.uri |
doi:10.1016/j.cell.2015.09.052 |
|
dc.description.abstract |
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. |
|
dc.relation.ispartof |
urn:issn:0092-8674 |
|
dc.title |
Timing of CFTR Pore Opening and Structure of Its Transition State |
|
dc.type |
Journal Article |
|
dc.date.updated |
2015-11-23T09:21:55Z |
|
dc.language.rfc3066 |
en |
|
dc.identifier.mtmt |
2964742 |
|
dc.identifier.pubmed |
26496611 |
|
dc.contributor.department |
SE/AOK/I/Orvosi Biokémiai Intézet |
|
dc.contributor.department |
SE/AOK/I/OBI/MTA-SE Lendület Ioncsatorna Kutatócsoport |
|
dc.contributor.institution |
Semmelweis Egyetem |
|