(A) CFTR is 1480 amino acids in length and contains two transmembrane domains (TMDs, orange and pink) and four intracellular loops (labeled ICL1–4, cyan, orange, blue, and yellow), two nucleotide binding domains (NBDs, grey and charcoal) and a highly disordered Regulatory region (R, purple). F508, green is located within the NBD1 domain. (B) The Sav1866 based homology model of CFTR sans R-region (pdbs 2HYD, 1R0W, and 3GD7). (top) View of the NBDs and ICLs of CFTR parallel to the membrane. The two NBDs associate in a head-to-tail fashion. ICL1 (cyan ribbon) and ICL4 (yellow ribbon) interact with NBD1 and ICL2 (orange ribbon) and ICL3 (blue ribbon) interact with NBD2. F508 (green surface) is at the predicted interface with ICL4. NBD1 surface residues predicted to be within 6 Å of ICL1, ICL4 or both are highlighted in cyan, yellow or light green respectively. (bottom) View of the CFTR model looking down from the membrane (90° relative to top). See also Figure S1. (C) Ribbon representation of NBD1 (pdb 1R0W) showing relationship of F508 (green sticks) to the predicted interface with ICL4 yellow outline.