A Homology-Based Molecular Model of the Closed State of Human CFTR

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-gated chloride channel belonging to the ATP-binding cassette (ABC) transporter superfamily of proteins, and the locus of the primary defect in cystic fibrosis (CF). Advances in CF therapeutic research have been hampered by the lack of information about the conformational changes that CFTR undergoes during its gating cycle. Here, we present an all-atom structural model of the inward-facing, ATP-free conformation of CFTR that is based on comparative/homology modeling using as a template the experimental structure of P-glycoprotein, a closely-related ABC transporter. We believe that this model, which is supported by experimental data, corresponds to the closed state of the CFTR channel, and it provides vital clues as to what makes CFTR unique as the only member of the ABC transporter superfamily that bears channel activity. Notably, the proposed structure is significantly different from prior homology models of nucleotide-bound CFTR, which have been proposed to represent the putative open state conformation. This homology model provides the basis for examining possible pathways as the CFTR structure moves between the closed and open states, which should lead to a better understanding of the relationship between molecular structure and channel function in CFTR.Support: NIH-DK056481 to N.A.M.