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  A molecular switch driving inactivation in the cardiac K+ channel hERG.

Köpfer, D., Hahn, U., Ohmert, I., Vriend, G., Pongs, O., de Groot, B. L., et al. (2012). A molecular switch driving inactivation in the cardiac K+ channel hERG. PLoS One, 7(7): e41023. doi:10.1371/journal.pone.0041023.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000F-A66D-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CD48-9
Genre: Journal Article

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PLoSone.0041023-2012.pdf (Publisher version), 905KB
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Köpfer, D.1, Author              
Hahn, U., Author
Ohmert, I., Author
Vriend, G., Author
Pongs, O., Author
de Groot, B. L.1, Author              
Zachariae, U.1, Author              
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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 Abstract: K+ channels control transmembrane action potentials by gating open or closed in response to external stimuli. Inactivation gating, involving a conformational change at the K+ selectivity filter, has recently been recognized as a major K+ channel regulatory mechanism. In the K+ channel hERG, inactivation controls the length of the human cardiac action potential. Mutations impairing hERG inactivation cause life-threatening cardiac arrhythmia, which also occur as undesired side effects of drugs. In this paper, we report atomistic molecular dynamics simulations, complemented by mutational and electrophysiological studies, which suggest that the selectivity filter adopts a collapsed conformation in the inactivated state of hERG. The selectivity filter is gated by an intricate hydrogen bond network around residues S620 and N629. Mutations of this hydrogen bond network are shown to cause inactivation deficiency in electrophysiological measurements. In addition, drug-related conformational changes around the central cavity and pore helix provide a functional mechanism for newly discovered hERG activators.

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Language(s): eng - English
 Dates: 2012-07-24
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1371/journal.pone.0041023
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Title: PLoS One
Source Genre: Journal
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Pages: - Volume / Issue: 7 (7) Sequence Number: e41023 Start / End Page: - Identifier: -