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PLoS One. 2013 Sep 27;8(9):e74574. doi: 10.1371/journal.pone.0074574. eCollection 2013.

Modeling the conformational changes underlying channel opening in CFTR.

Author information

1
Petit Institute of Bioengineering and Bioscience and School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

Abstract

Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) cause cystic fibrosis (CF), the most common life-shortening genetic disease among Caucasians. Although general features of the structure of CFTR have been predicted from homology models, the conformational changes that result in channel opening and closing have yet to be resolved. We created new closed- and open-state homology models of CFTR, and performed targeted molecular dynamics simulations of the conformational transitions in a channel opening event. The simulations predict a conformational wave that starts at the nucleotide binding domains and ends with the formation of an open conduction pathway. Changes in side-chain interactions are observed in all major domains of the protein, and experimental confirmation was obtained for a novel intra-protein salt bridge that breaks near the end of the transition. The models and simulation add to our understanding of the mechanism of ATP-dependent gating in this disease-relevant ion channel.

PMID:
24086355
PMCID:
PMC3785483
DOI:
10.1371/journal.pone.0074574
[Indexed for MEDLINE]
Free PMC Article

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