Cryo-EM structure of dephosphorylated, ATP-free CFTR. A. CFTR contains two transmembrane domains (TMD1 in orange, TMD2 in blue), two nucleotide binding domains (NBD1 in purple, NBD2 in yellow), and a regulatory (R) domain (cyan). CFTR is activated by phosphorylation of the R domain and ATP hydrolysis by the NBDs. Note that the structural flexibility of the R domain limits its visibility by Cryo-EM. Instead, 19 alanines are shown that correspond to the C-terminal region of the R domain. B. Magnified view of transmembrane helices (TM) 7 (brown) and 8 (gray). CFTR differs from other ABC transporters in that TM7 is displaced from its usual position and TM8 breaks into three short helices, rather than being a continuous helix as seen in other ABC transporters. TM7 and TM8 are found in TMD2. PBD ID: 5UAK.