(A) 3D organization of the CFTR gene – the so-called topologically associated domain – in airway cells, showing the promoter, the boundaries (I and II) and architectural proteins CTCF and cohesin (adapted from [23]). (B) Ribbon representation of the human CFTR 3D structure (ATP-bound, phosphorylated form) in complex with VX-770 (PDB: 6O2P [124]), illustrating striking features of the channel, as discussed in the text. The two ATP molecules are shown at the interface between NBD1 and NBD2. Transmembrane (TM) helices extend in the cytoplasm, forming long intracellular loops (ICLs) which contact the NBDs through coupling helices. ECL4 stands for extracellular loop 4. Fragment of the R domain was modeled as a poly-alanine into a density of the cryo-EM map (yellow). This figure (and Figure 2) was prepared using Chimera https://www.rbvi.ucsf.edu/chimera.