Modelling the restoration of wild-type dynamic behaviour in DeltaF508-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 DeltaF508) 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 DeltaF508-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 DeltaF508 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 DeltaF508-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.
Warner
Daniel J
DJ
Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
Vadolia
Manish M
MM
Laughton
Charles A
CA
Kerr
Ian D
ID
Doughty
Stephen W
SW
D000595:Amino Acid Sequence; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009711:Nucleotides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D014970:Xanthines / Q000737:chemistry*
D009711:Nucleotides; D014970:Xanthines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C051360:1,3-dipropyl-8-cyclopentylxanthine