Fig. 5: CFTR gating model.

Model of the wild-type CFTR gating cycle at physiological ATP concentration. Dephosphorylated CFTR adopts an NBD-separated, auto-inhibited conformation. At steady state, the NBDs of fully phosphorylated CFTR dimerize rapidly with ATP bound at both sites (step 1). Dimerization is followed by conformational change to enable pore opening (step 2) and ATP hydrolysis at the consensus site (step 3). During the pre-hydrolytic open burst, CFTR rapidly samples a flicker-closed state. Post-hydrolytic CFTR remains open, but eventually relaxes to a non-conductive dimerized state (step 4). ADP dissociation (step 5) leads to a dynamically isomerizing intermediate (step 7). ATP rebinding may occur with subtle rearrangement at the dimer interface (step 6) or with complete NBD separation (step 8) to initiate a new gating cycle.