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Cystic fibrosis transmembrane conductance regulator (CFTR): closed and open state channel models.

Corradi, V; Vergani, P; Tieleman, DP; (2015) Cystic fibrosis transmembrane conductance regulator (CFTR): closed and open state channel models. Journal of Biological Chemistry , 290 pp. 22891-22906. 10.1074/jbc.M115.665125. Green open access

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Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP binding cassette (ABC) transporter superfamily. CFTR controls the flow of anions through the apical membrane of epithelia. Dysfunctional CFTR causes the common lethal genetic disease cystic fibrosis. Transitions between open and closed states of CFTR are regulated by ATP binding and hydrolysis on the cystosolic nucleotide binding domains (NBDs), which are coupled with the transmembrane domains (TMDs) forming the pathway for anion permeation. Lack of structural data hampers a global understanding of CFTR, and thus the development of rational approaches directly targeting defective CFTR. In this work, we explored possible conformational states of the CFTR gating cycle by means of homology modeling. As templates, we used structures of homologous ABC transporters, namely TM287- 288, ABC-B10, McjD and Sav1866. In the light of published experimental results, structural analysis of the transmembrane cavity suggests that the TM287-288-based CFTR model could correspond to a commonly occupied closed state, while the McjD-based model could represent an open state. The models capture the important role played by Phe337 as a filter/gating residue and provide structural information on the conformational transition from closed to open channel.

Type: Article
Title: Cystic fibrosis transmembrane conductance regulator (CFTR): closed and open state channel models.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.M115.665125
Publisher version: http://dx.doi.org/10.1074/jbc.M115.665125
Language: English
Additional information: This article is published under a Creative Commons Attribution 4.0 International license (CC BY 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at http://creativecommons.org/ licenses/by/4.0
Keywords: ABC transporter, chloride transport, cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR), molecular modeling
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1471166
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