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Cell Mol Life Sci. 2009 Nov;66(21):3469-86. doi: 10.1007/s00018-009-0133-0. Epub 2009 Aug 26.

Molecular models of the open and closed states of the whole human CFTR protein.

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IMPMC, UMR7590, CNRS, Universit├ęs Pierre et Marie Curie-Paris 6 et Denis Diderot-Paris 7, 140 Rue de Lourmel, Paris, France.


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.

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