Molecular models of the open and closed states of the whole human CFTR protein.
Cystic fibrosis transmembrane conductance regulator (CFTR), involved in cystic fibrosis (CF), is a chloride channel belonging to the ATP-binding cassette (ABC) superfamily. Using the experimental structure of Sav1866 as template, we previously modeled the human CFTR structure, including membrane-spanning domains (MSD) and nucleotide-binding domains (NBD), in an outward-facing conformation (open channel state). Here, we constructed a model of the CFTR inward-facing conformation (closed channel) on the basis of the recent corrected structures of MsbA and compared the structural features of those two states of the channel. Interestingly, the MSD:NBD coupling interfaces including F508 (DeltaF508 being the most common CF mutation) are mainly left unchanged. This prediction, completed by the modeling of the regulatory R domain, is supported by experimental data and provides a molecular basis for a better understanding of the functioning of CFTR, especially of the structural features that make CFTR the unique channel among the ABC transporters.
Mornon
Jean-Paul
JP
IMPMC, UMR7590, CNRS, Universités Pierre et Marie Curie-Paris 6 et Denis Diderot-Paris 7, 140 Rue de Lourmel, Paris, France. jean-paul.mornon@impmc.jussieu.fr
Lehn
Pierre
P
Callebaut
Isabelle
I
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry; D000595:Amino Acid Sequence; D003198:Computer Simulation; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D018528:ATP-Binding Cassette Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
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