Figure 1.

CFTR topology and gating cycle.

(A) Cartoon topology of CFTR. TMD1–2, gray; NBD1, blue; NBD2, green; R-domain, pale red. Red asterisk denotes catalytic site mutations. (B) Cartoon of head-to-tail NBD dimer. Color coding as in (A). ATP, large yellow circles. Site 2 (top): conserved Walker A/B residues, small red circles; catalytic base, small black circle; signature sequence, magenta crescent. Site 1 (bottom): color coding as for site 2, pale residues represent non-conserved substitutions. Residue numbering corresponds to the human CFTR sequence. (C) Schematic gating cycle of phosphorylated CFTR. Flickery closures from states B₁ and B₂ are not depicted. Disruption of ATP hydrolysis in catalytic site mutants (red cross) reduces gating to reversible IB₁ ↔ B₁ transitions (red box). Note, that in reality sites 1 and 2 are equally near the membrane, in the cartoons site 2 is depicted as the top and site 1 as the bottom site merely for representation purposes.