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Modeling the Conformational Changes Underlying Channel Opening in CFTR
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 conform...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785483/ https://www.ncbi.nlm.nih.gov/pubmed/24086355 http://dx.doi.org/10.1371/journal.pone.0074574 |
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author | Rahman, Kazi S. Cui, Guiying Harvey, Stephen C. McCarty, Nael A. |
author_facet | Rahman, Kazi S. Cui, Guiying Harvey, Stephen C. McCarty, Nael A. |
author_sort | Rahman, Kazi S. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3785483 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37854832013-10-01 Modeling the Conformational Changes Underlying Channel Opening in CFTR Rahman, Kazi S. Cui, Guiying Harvey, Stephen C. McCarty, Nael A. PLoS One Research Article 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. Public Library of Science 2013-09-27 /pmc/articles/PMC3785483/ /pubmed/24086355 http://dx.doi.org/10.1371/journal.pone.0074574 Text en © 2013 Rahman et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Rahman, Kazi S. Cui, Guiying Harvey, Stephen C. McCarty, Nael A. Modeling the Conformational Changes Underlying Channel Opening in CFTR |
title | Modeling the Conformational Changes Underlying Channel Opening in CFTR |
title_full | Modeling the Conformational Changes Underlying Channel Opening in CFTR |
title_fullStr | Modeling the Conformational Changes Underlying Channel Opening in CFTR |
title_full_unstemmed | Modeling the Conformational Changes Underlying Channel Opening in CFTR |
title_short | Modeling the Conformational Changes Underlying Channel Opening in CFTR |
title_sort | modeling the conformational changes underlying channel opening in cftr |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785483/ https://www.ncbi.nlm.nih.gov/pubmed/24086355 http://dx.doi.org/10.1371/journal.pone.0074574 |
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