Time-asymmetric conductance pattern of CFTR correlates with its ATP hydrolytic activity. (A) Illustration of the O1-O2 phenotype. Schematic representation of single-channel current for a typical single open (burst) event, illustrating the two subconductance levels in their preferential order. (B) Cartoon representation of pre- (left) and posthydrolytic (right) open states of a CFTR channel. Arrows between the two states reflect the preferential order in which they are visited in each burst, as a consequence of a nonequilibrium gating cycle. TMDs, yellow; NBD1, red; NBD2, blue; ATP, green; ADP + phosphate, blue oval + red crescent; chloride ions, black spheres; water molecules, blue. The canonical ATP-binding site is depicted as the top site in the NBDs, and the noncanonical site is shown at the bottom. Red stars in the TMDs represent mutations that disturb the local charge distribution. In the posthydrolytic state, a suggested expansion of the internal vestibule results in the accommodation of a larger number of water molecules, which dampen the negative impact of the mutations on chloride throughput rate (stronger double arrows bracketing the chain of chloride ions).
