Molecular models of the open and closed states of

Authors: JeanPaul Mornon Pierre Lehn Isabelle Callebaut

Publish Date: 2009/08/26

Volume: 66, Issue: 21, Pages: 3469-3486

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Abstract

Cystic fibrosis transmembrane conductance regulator CFTR involved in cystic fibrosis CF is a chloride channel belonging to the ATPbinding cassette ABC superfamily Using the experimental structure of Sav1866 as template we previously modeled the human CFTR structure including membranespanning domains MSD and nucleotidebinding domains NBD in an outwardfacing conformation open channel state Here we constructed a model of the CFTR inwardfacing 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 MSDNBD coupling interfaces including F508 ΔF508 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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