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

Köpfer DA, Hahn U, Ohmert I, Vriend G, Pongs O, de Groot BL, Zachariae U - PLoS ONE (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.

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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Related in: MedlinePlus

Suggested mechanism of action for hERG activators.(A) Binding pocket for activators, shown here located between the pore helices of two adjacent subunits (orange surface). (B) The experimentally determined binding pocket for PD-118057 and ICA-105574 is located around residue F619 and extends to residue L622 (secondary subunit contacts are marked with a prime symbol). (C) A cascade of conformational changes triggered by collapse of the SF leads to constriction of the binding pocket (orange lines) and rearrangement of L622. (D) The cavity is large enough to accommodate PD-118057. All residues known to affect PD-118057 binding [23] line the pocket (yellow). (E) The activator molecule ICA-105574, shown docked to the side-pocket with residues known to influence binding in yellow.
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pone-0041023-g005: Suggested mechanism of action for hERG activators.(A) Binding pocket for activators, shown here located between the pore helices of two adjacent subunits (orange surface). (B) The experimentally determined binding pocket for PD-118057 and ICA-105574 is located around residue F619 and extends to residue L622 (secondary subunit contacts are marked with a prime symbol). (C) A cascade of conformational changes triggered by collapse of the SF leads to constriction of the binding pocket (orange lines) and rearrangement of L622. (D) The cavity is large enough to accommodate PD-118057. All residues known to affect PD-118057 binding [23] line the pocket (yellow). (E) The activator molecule ICA-105574, shown docked to the side-pocket with residues known to influence binding in yellow.

Mentions: The conformational change at the SF initially had a moderate direct spatial extent (initial RMSD in the SF: 1 Å). Intriguingly however, it had far-ranging subsequent consequences near the pore helix and the interface with S6 in the trajectories: The subtle conformational change within the backbone of the SF (S624-G628) was gradually amplified by inducing side chain rotations, in particular those of V625 and F627. This reordering led to rotation of the directly neighboring residue L622 on the pore helix and the main drug binding site F619, one helical turn upward. In concert, these rearrangements in the activated open state were found to be capable of opening a side pocket, extending from the main cavity (Fig. 5 A,B), which was found to be wide enough to accommodate either PD-118057 and ICA-105574 in molecular docking calculations. In contrast, the pocket was smaller and only transiently present in the inactivated state, blocking their entry (Fig. 5 C).


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

Köpfer DA, Hahn U, Ohmert I, Vriend G, Pongs O, de Groot BL, Zachariae U - PLoS ONE (2012)

Suggested mechanism of action for hERG activators.(A) Binding pocket for activators, shown here located between the pore helices of two adjacent subunits (orange surface). (B) The experimentally determined binding pocket for PD-118057 and ICA-105574 is located around residue F619 and extends to residue L622 (secondary subunit contacts are marked with a prime symbol). (C) A cascade of conformational changes triggered by collapse of the SF leads to constriction of the binding pocket (orange lines) and rearrangement of L622. (D) The cavity is large enough to accommodate PD-118057. All residues known to affect PD-118057 binding [23] line the pocket (yellow). (E) The activator molecule ICA-105574, shown docked to the side-pocket with residues known to influence binding in yellow.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404103&req=5

pone-0041023-g005: Suggested mechanism of action for hERG activators.(A) Binding pocket for activators, shown here located between the pore helices of two adjacent subunits (orange surface). (B) The experimentally determined binding pocket for PD-118057 and ICA-105574 is located around residue F619 and extends to residue L622 (secondary subunit contacts are marked with a prime symbol). (C) A cascade of conformational changes triggered by collapse of the SF leads to constriction of the binding pocket (orange lines) and rearrangement of L622. (D) The cavity is large enough to accommodate PD-118057. All residues known to affect PD-118057 binding [23] line the pocket (yellow). (E) The activator molecule ICA-105574, shown docked to the side-pocket with residues known to influence binding in yellow.
Mentions: The conformational change at the SF initially had a moderate direct spatial extent (initial RMSD in the SF: 1 Å). Intriguingly however, it had far-ranging subsequent consequences near the pore helix and the interface with S6 in the trajectories: The subtle conformational change within the backbone of the SF (S624-G628) was gradually amplified by inducing side chain rotations, in particular those of V625 and F627. This reordering led to rotation of the directly neighboring residue L622 on the pore helix and the main drug binding site F619, one helical turn upward. In concert, these rearrangements in the activated open state were found to be capable of opening a side pocket, extending from the main cavity (Fig. 5 A,B), which was found to be wide enough to accommodate either PD-118057 and ICA-105574 in molecular docking calculations. In contrast, the pocket was smaller and only transiently present in the inactivated state, blocking their entry (Fig. 5 C).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.

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.

Show MeSH
Related in: MedlinePlus