Modelling the restoration of wild-type dynamic behaviour in ?F508-CFTR NBD1 by 8-cyclopentyl-1,3-dipropylxanthine
Cystic fibrosis (CF) is the most frequently occurring severe, genetic disease in western populations with an incidence as high as 1 in 2500. The principal biochemical defect in CF is a mutation in a membrane transport protein, namely the cystic fibrosis transmembrane conductance regulator (CFTR), which is responsible for the conductance of chloride ions across cell membranes. In 70% of cases a single mutation in CFTR, namely the deletion of amino acid 508 (called ?F508) is sufficient to cause severe disease. This mutation manifests as a failure of the protein to be effectively targeted to the membrane. Recently, it has been shown that small molecule drug therapy can restore the membrane-targeting of ?F508-CFTR, where the mutant channel functions adequately. We have created models of the first nucleotide-binding domain (NBD1) region (which houses the proposed binding site of these restorative drugs) of the wild-type and mutant forms of human CFTR. We have simulated the dynamical behaviour of these proteins in the presence of drugs that restore trafficking of the protein. Our results indicate that there are particular modes of dynamic motion that are distinguishable between wild-type and mutant CFTR. These regions of motion are localized in the regions of the ?F508 mutation and the drug-binding regions. The simulations of drug binding indicate that wild-type dynamic motions are restored in these regions. We conclude therefore that these drugs are able to alter the dynamic properties of ?F508-CFTR such that the drug-bound mutant protein more closely resembles the wild-type protein dynamic behaviour, and hence we hypothesize that it is this that allows for correct targeting to the membrane.
?f508 deletion phe-508 abc atp-binding cassette cf cystic fibrosis cftr cystic fibrosis transmembrane conductance regulator cpx 8-cyclopentyl-1 3-dipropylxanthine md molecular dynamics msd1/msd2 membrane-spanning domains 1&2 nbd1/nbd2 nucleotide-binding domains 1&2 pca principal component analysis rmsd root mean square deviation rmsip root mean square inner product