Fig. 2. –

A simplified model showing the mechanism of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) activation by physiological stimuli (a) and correction of gating defect by CFTR potentiators (b). In normal cells, CFTR activation is obtained by phosphorylation of the R domain by the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PK)A and binding of adenosine triphosphate (ATP) molecules to nucleotide binding domains. It is possible that the formation of a nucleotide-binding domain (NBD) dimer is required for CFTR pore opening and chloride ion transport. In mutant CFTR (b), mutations like G551D probably impair the mechanism of activation by altering the conformation of NBDs. CFTR potentiators, e.g. genistein may determine a normalisation of NBD structure/function with the opening of the channel. The figure shows binding of potentiator to the interface between NBDs with consequent structural change of one ATP binding site. This is hypothetical since the mechanism of CFTR potentiators still needs to be clarified. P: phosphate.