Early Steps in C-Type Inactivation of the hERG Potassium Channel

Pettini, Francesco; Domene, Carmen; Furini, Simone

doi:10.1021/acs.jcim.2c01028

Cited by 9 publications

(8 citation statements)

References 44 publications

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“…Previously, a similar effect was noticed by Jensen & Shaw in their remarkable in silico simulation of voltage gating of a K v [35]. SF reveals to be a surprisingly stable structure, deviating from the almost ideal square- antiprismatic geometry only upon C-type inactivation (our unpublished analysis), which, however, is likely to occur in hERG [55,56]. It is not clear whether this structural alteration would affect BeKm-1 binding, since the toxin interacts with the regions above the SF, although it is assumed to interfere with the binding of some small molecules [57].…”

Section: Discussionsupporting

confidence: 83%

The scorpion toxin BeKm‐1 blocks hERG cardiac potassium channels using an indispensable arginine residue

Zavarzina,

Kuzmenkov,

Dobrokhotov

et al. 2024

FEBS Letters

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BeKm‐1 is a peptide toxin from scorpion venom that blocks the pore of the potassium channel hERG (Kv11.1) in the human heart. Although individual protein structures have been resolved, the structure of the complex between hERG and BeKm‐1 is unknown. Here, we used molecular dynamics and ensemble docking, guided by previous double‐mutant cycle analysis data, to obtain an in silico model of the hERG–BeKm‐1 complex. Adding to the previous mutagenesis study of BeKm‐1, our model uncovers the key role of residue Arg20, which forms three interactions (a salt bridge and hydrogen bonds) with the channel vestibule simultaneously. Replacement of this residue even by lysine weakens the interactions significantly. In accordance, the recombinantly produced BeKm‐1R20K mutant exhibited dramatically decreased activity on hERG. Our model may be useful for future drug design attempts.

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Section: Discussionsupporting

confidence: 83%

The scorpion toxin BeKm‐1 blocks hERG cardiac potassium channels using an indispensable arginine residue

Zavarzina,

Kuzmenkov,

Dobrokhotov

et al. 2024

FEBS Letters

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“…The published structures for the “inactivated” state of Shaker, however, are based on mutant structures, rather than changes in K + concentration. In a recent MD simulation study of HERG, Pettini and colleagues showed that mutants that promoted inactivation led to widening of the extracellular entrance of the channel, but less prominent than what was seen in Shaker 25 . In our cryo-EM structures we observed a small dilatation of the upper filter, in both the high-K and low-K structures ( Supplementary Fig S5 ).…”

Section: Discussionmentioning

confidence: 99%

“…The authors suggested that such a subtle structural change was consistent with the rapidity of inactivation in HERG 22 . Conversely, Molecular dynamics (MD) simulation studies of the WT HERG structure suggested that the transition from conducting to non-conducting selectivity filter structures could involve asymmetric buckling of the selectivity filter 23,24 , and/or dilation of the upper filter 23,25 . An alternative explanation for the similarity of the WT and S631A HERG structures is that they both represent subtly different conductive state structures 23,26,27 .…”

Section: Introductionmentioning

confidence: 99%

Potassium dependent structural changes in the selectivity filter of HERG potassium channels

Lau,

Flood,

Hunter

et al. 2023

Preprint

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The fine tuning of biological electrical signaling is mediated by variations in the rates of opening and closing of gates that control ion flux through different ion channels. Human ether-a-go-go related gene (HERG) potassium channels have uniquely rapid inactivation kinetics which are critical to the role they play in regulating cardiac electrical activity. Here, we have exploited the K+sensitivity of HERG inactivation to determine structures of both a conductive and non-conductive selectivity filter structure of HERG. We propose that inactivation is the result of a high propensity for flipping of the selectivity filter valine carbonyl oxygens. Molecular dynamics simulations point to a low energy barrier, and hence rapid kinetics, for flipping of the valine 625 carbonyl oxygens facilitated by a previously unrecognized interaction between S620 and Y616 that stabilizes the transition state between conducting and non-conducting structures. Our model represents a new mechanism by which ion channels fine tune their activity that explains the uniquely rapid inactivation kinetics of HERG.HighlightsStructures of a conductive and non-conductive HERG selectivity filter have been determined.Reduced potassium causes flipping of selectivity filter valine carbonyl oxygens.The sidechain of S620 on the pore helix coordinates distinct sets of interactions between conductive, non-conductive, and transition states.

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“…Having shown that ICA-105574 can rescue the activity of G628S and A561V but not that of L779P in vitro , we set out to understand the molecular determinants of this rescue mechanism using MD simulations. Previous work on the hERG channel showed rapid inactivation on the ns time scale for the wild-type protein, making it difficult to accumulate extensive statistics on the conformational dynamics of the hERG active state (16, 17, 37). Here we started with a known cryo-EM structure (PDB ID: 5VA2) determined in the active state for the wild type ( Figure 3A ), including the PAS domain (15), in a POPC bilayer with 200 mM salt concentration (KCl) and applied transmembrane voltage ranging from ∼650 mV to ∼750 mV.…”

Section: Resultsmentioning

confidence: 99%

Molecular Insights into the Rescue Mechanism of an hERG Activator Against Severe LQT2 Mutations

Kumawat,

Tavazzani,

Lentini

et al. 2024

Preprint

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Mutations in the hERG potassium channel are a major cause of long QT syndrome type 2 (LQT2), which can lead to sudden cardiac death. The hERG channel plays a critical role in the repolarization of the myocardial action potential, and loss-of-function mutations prolong cardiac repolarization. In this study, we investigated the efficacy and mechanism of ICA-105574, an hERG activator, in shortening the duration of cardiac repolarization in severe LQT2 variants. We characterized the in vivo efficacy of ICA-105574 in shortening the QT duration in an animal model and the in vitroIKrcurrent in cellular models mimicking severe hERG channel mutations (A561V, G628S, and L779P). We then used molecular dynamics simulations to investigate the molecular mechanisms of ICA-105574 action. In vivo, ICA-105574 significantly shortened the QT interval. LQT2 mutations drastically reducedIKramplitude and suppressed tail currents in cellular models. ICA-105574 restoredIKrin A561V and G628S. Finally, in silico data showed that ICA-105574 stabilizes a pattern of interactions similar to gain-of-function SQT1 mutations and can reverse the G628S modifications, through an allosteric network linking the binding site to the selectivity filter and the S5P turret helix, thereby restoring its K+ion permeability. Our results support the development of hERG activators as pharmacological molecules against some severe LQT2 mutations and suggest that molecular dynamics simulations can be used to test the ability of molecules to modulate hERG function in silico, paving the way for the rational design of new hERG activators.Significance StatementLong QT syndrome 2 (LQT2) results fromKCNH2gene mutations that affect the hERG channel, which is critical for cardiac repolarization. To investigate the therapeutic potential of ICA-105574, we used in vivo, in vitro and in silico models. In vivo, ICA-105574 significantly shortened the QT interval. In vitro, ICA-105574 selectively increased hERG current amplitude in severe LQT2 mutations (A561V, G628S) but not in L779P. Ourin-silicoanalysis suggests a potential mechanism, similar to SQT1 mutations, modulating an allosteric network linking the ICA-105574 binding site to the selectivity filter and the S5P turret helix. These findings deepen the understanding of hERG activation and suggest a potential therapeutic approach for LQT2.

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Early Steps in C-Type Inactivation of the hERG Potassium Channel

Cited by 9 publications

References 44 publications

The scorpion toxin BeKm‐1 blocks hERG cardiac potassium channels using an indispensable arginine residue

The scorpion toxin BeKm‐1 blocks hERG cardiac potassium channels using an indispensable arginine residue

Potassium dependent structural changes in the selectivity filter of HERG potassium channels

Molecular Insights into the Rescue Mechanism of an hERG Activator Against Severe LQT2 Mutations

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