We have presented a new
protein-
protein docking approach to model heterodimeric structures based on the conformations of the monomeric units. The conventional modeling method relies on superimposing two monomeric structures onto the crystal structure of a homologous
protein dimer. The resulting structure may exhibit severe backbone clashes at the dimeric interface depending on the backbone dissimilarity between the target and template
proteins. Our method overcomes the backbone clashing problem and requires no a priori knowledge of the dimeric structure of a homologous
protein. Here we used human
Cystic Fibrosis Transmembrane conductance Regulator (CFTR), a
chloride channel whose dysfunction causes
cystic fibrosis, for illustration. The two intracellular
nucleotide-binding domains (NBDs) of CFTR control the opening and closing of the channel. Yet, the structure of the CFTR's NBD1-NBD2 complex has not been experimentally determined. Thus, correct modeling of this heterodimeric structure is valuable for understanding CFTR functions and would have potential applications for drug design for
cystic fibrosis treatment. Based on the crystal structure of human CFTR's NBD1, we constructed a model of the NBD1-NBD2 complex. The constructed model is consistent with the dimeric mode observed in the crystal structures of other
ABC transporters. To verify our structural model, an
ATP substrate was docked into the
nucleotide-binding site. The predicted binding mode shows consistency with related crystallographic findings and CFTR functional studies. Finally,
genistein, an agent that enhances CFTR activity, though the mechanism for such enhancement is unclear, was docked to the model. Our predictions agreed with
genistein's bell-shaped dose-response relationship. Potential mutagenesis experiments were proposed for understanding the potentiation mechanism of
genistein and for providing insightful information for drug design targeting at CFTR. The method used in this study can be applied to modeling studies of other dimeric
protein structures.