The dimeric mode of our constructed human CFTR’s NBD1– NBD2 structure is consistent with the unique head-to-tail dimeric modes found in the crystal structures of other members in the ABC transporter superfamily. The predicted binding mode of the substrate (i.e., ATP) also shows consistency with the binding mode observed in the crystal structures of other ABC transporters and in functional studies of CFTR. In contrast, direct superimposition of the monomeric structures onto the crystal structure of the NBD homodimer of another member in the ABC transporter family may cause severe backbone clashes at the dimeric interface and leave insufficient space for ATP to bind.