Dynamics of the EAG1 K + channel selectivity filter assessed by molecular dynamics simulations

Bernsteiner, Harald; Bründl, Michael; Stary-Weinzinger, Anna

doi:10.1016/j.bbrc.2017.01.064

Cited by 3 publications

(3 citation statements)

References 38 publications

(74 reference statements)

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“…Simulations on hERG homology models suggest that the SF of ether- à -go-go (EAG) K + channel family members, including hERG, hEAG, and human ether- à -go-go like (hELK) channels, might be uniquely flexible compared to other voltage-gated K + channels. , Our recent simulation studies on the hEAG1 cryoelectron microscopy (cryo-EM) structure support this notion . Rotation of several carbonyl oxygen atoms of the outermost ion coordination site (S0) in the SF destroyed the ability to favorably coordinate K + ions.…”

Section: Introductionmentioning

confidence: 97%

“…25,34 Our recent simulation studies on the hEAG1 cryoelectron microscopy (cryo-EM) structure support this notion. 35 Rotation of several carbonyl oxygen atoms of the outermost ion coordination site (S0) in the SF destroyed the ability to favorably coordinate K + ions. These changes induce a widening of the filter in the S0 region and likely represent a nonconductive filter configuration that may approximate the hypothesized early conformational changes linked to C-type inactivation.…”

Section: ■ Introductionmentioning

confidence: 99%

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Toward a Structural View of hERG Activation by the Small-Molecule Activator ICA-105574

Zangerl-Plessl

Berger

Drescher

et al. 2019

J. Chem. Inf. Model.

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Outward current conducted by human ether-à-go-go-related gene type 1 (hERG1) K+ channels is important for action potential repolarization in the human ventricle. Rapid, voltage-dependent inactivation greatly reduces outward currents conducted by hERG1 channels and involves conformational changes in the ion selectivity filter (SF). Recently, compounds have been found that activate hERG1 channel function by modulating gating mechanisms such as reducing inactivation. Such activating compounds could represent a novel approach to prevent arrhythmias associated with prolonged ventricular repolarization associated with inherited or acquired long QT syndrome. ICA-105574 (ICA), a 3-nitro-n-(4-phenoxyphenyl) benzamide derivative activates hERG1 by strongly attenuating pore-type inactivation. We previously mapped the putative binding site for ICA to a hydrophobic pocket located between two adjacent subunits. Here, we used the recently reported cryoelectron microscopy structures of hERG1 to elucidate the structural mechanisms by which ICA influences the stability of the SF. By combining molecular dynamics simulations, voltage-clamp electrophysiology, and the synthesis of novel ICA derivatives, we provide atomistic insights into SF dynamics and propose a structural link between the SF and S6 segments. Further, our study highlights the importance of the nitro moiety, at the meta position of the benzamide ring, for the activity of ICA and reveals that the (bio)isosteric substitution of this side chain can switch the activity to weak inhibitors. Our findings indicate that ICA increases the stability of the SF to attenuate channel inactivation, and this action requires a fine-tuned compound geometry.

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Section: Introductionmentioning

confidence: 97%

Section: ■ Introductionmentioning

confidence: 99%

Toward a Structural View of hERG Activation by the Small-Molecule Activator ICA-105574

Zangerl-Plessl

Berger

Drescher

et al. 2019

J. Chem. Inf. Model.

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“…The hERG is particularly prone to blocking due to its large central cavity, which can easily accommodate many types of blockers . This cavity is lined by the S6 and S5 helices, but also by the perimembrane selectivity filter‐forming (H5) domain, from all its four identical alpha subunits . Clofilium, a class III antiarrhythmic agent (Figure A) owes its effects to blocking hERG currents with high affinity (IC 50 =2 nM) and its binding determinants (Figure B) have been identified through experimental mutagenesis .…”

Section: Introductionmentioning

confidence: 99%

Computer Simulations Reveal a Novel Blocking Mode of the hERG Ion Channel by the Antiarrhythmic Agent Clofilium

Șterbuleac

Maniu

2018

Molecular Informatics

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The binding modes of many hERG ion channel blockers are well understood, but a notable exception is clofilium, a potent antiarrhythmic agent whose action relies on blocking the current mediated by hERG. From the previously hypothesized binding modes of clofilium to hERG, only two can explain most of the experimental results. In this study, computer simulations are performed in order to analyze the hypothesized binding modes and to identify the consensus one. This is accomplished by employing molecular dynamics (MD) simulations and interaction energy calculations. The results show an unexpected binding mode, in which the quaternary nitrogen is placed in the upper part of the inner cavity, interacting strongly with Ser624, while the chlorophenyl group is located in the lower part, in better agreement with previous experimental results. This novel binding position also explains the higher affinity of clofilium for the related hEag1 channel and was correlated with the possibility that potent hERG blockers interact in specific ways with the residues near the intracellular activation gate, offering a new explanation that could help predict the potency of other hERG-blocking compounds.

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Selectivity filter modalities and rapid inactivation of the hERG1 channel

Miranda

DeMarco

Guo

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The human ether-á-go-go–related gene (hERG1) channel conducts small outward K+ currents that are critical for cardiomyocyte membrane repolarization. The gain-of-function mutation N629D at the outer mouth of the selectivity filter (SF) disrupts inactivation and K+-selective transport in hERG1, leading to arrhythmogenic phenotypes associated with long-QT syndrome. Here, we combined computational electrophysiology with Markov state model analysis to investigate how SF-level gating modalities control selective cation transport in wild-type (WT) and mutant (N629D) hERG1 variants. Starting from the recently reported cryogenic electron microscopy (cryo-EM) open-state channel structure, multiple microseconds-long molecular-dynamics (MD) trajectories were generated using different cation configurations at the filter, voltages, electrolyte concentrations, and force-field parameters. Most of the K+ permeation events observed in hERG1-WT simulations occurred at microsecond timescales, influenced by the spontaneous dehydration/rehydration dynamics at the filter. The SF region displayed conductive, constricted, occluded, and dilated states, in qualitative agreement with the well-documented flickering conductance of hERG1. In line with mutagenesis studies, these gating modalities resulted from dynamic interaction networks involving residues from the SF, outer-mouth vestibule, P-helices, and S5–P segments. We found that N629D mutation significantly stabilizes the SF in a state that is permeable to both K+ and Na+, which is reminiscent of the SF in the nonselective bacterial NaK channel. Increasing the external K+ concentration induced “WT-like” SF dynamics in N629D, in qualitative agreement with the recovery of flickering currents in experiments. Overall, our findings provide an understanding of the molecular mechanisms controlling selective transport in K+ channels with a nonconventional SF sequence.

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Dynamics of the EAG1 K + channel selectivity filter assessed by molecular dynamics simulations

Cited by 3 publications

References 38 publications

Toward a Structural View of hERG Activation by the Small-Molecule Activator ICA-105574

Toward a Structural View of hERG Activation by the Small-Molecule Activator ICA-105574

Computer Simulations Reveal a Novel Blocking Mode of the hERG Ion Channel by the Antiarrhythmic Agent Clofilium

Selectivity filter modalities and rapid inactivation of the hERG1 channel

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