A molecular switch driving inactivation in the cardiac K+ channel HERG.
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A molecular switch driving inactivation in the cardiac K+ channel HERG. / Köpfer, David A; Hahn, Ulrike; Ohmert, Iris; Vriend, Gert; Pongs, Olaf; Groot, de; Bert, L; Zachariae, Ulrich.
In: PLOS ONE, Vol. 7, No. 7, 7, 2012, p. 41023.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A molecular switch driving inactivation in the cardiac K+ channel HERG.
AU - Köpfer, David A
AU - Hahn, Ulrike
AU - Ohmert, Iris
AU - Vriend, Gert
AU - Pongs, Olaf
AU - Groot, de
AU - Bert, L
AU - Zachariae, Ulrich
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Protein Structure, Tertiary
KW - Mutation, Missense
KW - Amino Acid Substitution
KW - Xenopus laevis
KW - Arrhythmias, Cardiac/genetics/metabolism
KW - Ether-A-Go-Go Potassium Channels/chemistry/genetics/metabolism
KW - Hydrogen Bonding
KW - Molecular Dynamics Simulation
KW - Muscle Proteins/chemistry/genetics/metabolism
KW - Myocardium/chemistry/metabolism
KW - Animals
KW - Humans
KW - Protein Structure, Tertiary
KW - Mutation, Missense
KW - Amino Acid Substitution
KW - Xenopus laevis
KW - Arrhythmias, Cardiac/genetics/metabolism
KW - Ether-A-Go-Go Potassium Channels/chemistry/genetics/metabolism
KW - Hydrogen Bonding
KW - Molecular Dynamics Simulation
KW - Muscle Proteins/chemistry/genetics/metabolism
KW - Myocardium/chemistry/metabolism
U2 - 10.1371/journal.pone.0041023
DO - 10.1371/journal.pone.0041023
M3 - SCORING: Journal article
VL - 7
SP - 41023
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 7
M1 - 7
ER -
