Open-state structure and pore gating mechanism of the cardiac sodium channel

Jiang, Dequan; Banh, Richard L.; El-Din, Tamer M. Gamal; Tonggu, Lige; Lenaeus, Michael J.; Pomès, Régis; Zheng, Ning; Catterall, William A.

doi:10.1016/j.cell.2021.08.021

Cited by 70 publications

(102 citation statements)

References 74 publications

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“…Two residues in domain IV-S6 (F1760 and Y1767 in human Na V 1.5) have been shown to play a critical role in mediating the use-dependent block of these drugs ( Ragsdale et al, 1994 ). Cryo-EM structures of human and rat Na V 1.5 with anti-arrhythmic drugs classes IA (quinidine) ( Figure 3D ) and IC (propafenone) ( Figure 3E ) confirm that these drugs bind to the domain I-S6 and the domain IV-S6 segments and interact with the conserved F1760 side chain (human Na V 1.5 numbering) in domain IV-S6 via a π-π interaction ( Jiang et al, 2020 ; Jiang et al, 2021a ; Li et al, 2021 ). The structures also show the drugs interacting with Y1767 as has been suggested by previous electrophysiology and mutagenesis studies ( Ragsdale et al, 1996 ).…”

Section: Natural Druggability Of Voltage-gated Sodium Channelsmentioning

confidence: 83%

“…Fast inactivation is essentially triggered by the activation of VSD4 that couples the movement of S4 to the S4-S5 linker that forms the receptor site for the IFM motif to allosterically close the pore. The binding of the IFM motif squeezes S6 of domain III and IV by ∼2–∼6 Å, respectively ( Jiang et al, 2020 ; Jiang et al, 2021a ), to tilt inward toward the pore axis and close the activation gate ( Figure 2B ).…”

Section: State-dependent Structure and Function Of Voltage‐gated Sodi...mentioning

confidence: 99%

“…Na V drugs that have been approved by the FDA and are being used in the clinics are pore blockers that target the pore domain and occlude the sodium permeation pathway to stop sodium influx ( Gamal El-Din et al, 2018b ; Jiang et al, 2020 ; Jiang et al, 2021a ; Li et al, 2021 ). These are local anesthetic (i.e., lidocaine, benzocaine, etc.…”

Section: Innovative Druggability Of Voltage-gated Sodium Channelsmentioning

confidence: 99%

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Druggability of Voltage-Gated Sodium Channels—Exploring Old and New Drug Receptor Sites

Wisedchaisri

El-Din

2022

Front. Pharmacol.

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Voltage-gated ion channels are important drug targets because they play crucial physiological roles in both excitable and non-excitable cells. About 15% of clinical drugs used for treating human diseases target ion channels. However, most of these drugs do not provide sufficient specificity to a single subtype of the channels and their off-target side effects can be serious and sometimes fatal. Recent advancements in imaging techniques have enabled us for the first time to visualize unique and hidden parts of voltage-gated sodium channels in different structural conformations, and to develop drugs that further target a selected functional state in each channel subtype with the potential for high precision and low toxicity. In this review we describe the druggability of voltage-gated sodium channels in distinct functional states, which could potentially be used to selectively target the channels. We review classical drug receptors in the channels that have recently been structurally characterized by cryo-electron microscopy with natural neurotoxins and clinical drugs. We further examine recent drug discoveries for voltage-gated sodium channels and discuss opportunities to use distinct, state-dependent receptor sites in the voltage sensors as unique drug targets. Finally, we explore potential new receptor sites that are currently unknown for sodium channels but may be valuable for future drug discovery. The advancement presented here will help pave the way for drug development that selectively targets voltage-gated sodium channels.

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Section: Natural Druggability Of Voltage-gated Sodium Channelsmentioning

confidence: 83%

Section: State-dependent Structure and Function Of Voltage‐gated Sodi...mentioning

confidence: 99%

Section: Innovative Druggability Of Voltage-gated Sodium Channelsmentioning

confidence: 99%

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Druggability of Voltage-Gated Sodium Channels—Exploring Old and New Drug Receptor Sites

Wisedchaisri

El-Din

2022

Front. Pharmacol.

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“…These include, but not limited to, phosphorylation, glycosylation, palmitoylation, ubiquitination, and methylation (Pei et al, 2018). The advancement of CryoEM technology enabled us to visualize a wide variety of eukaryotic Na V structures, starting from cockroach (Na v Pas) (Shen et al, 2017), electric eel (Na v 1.4) (Yan et al, 2017), rat heart (Na v 1.5 in apo, drug-bound, and mutant forms) (Jiang et al, 2021;Jiang et al, 2020), to human brain (Na v 1.2), muscle (Na v 1.4) (Pan et al, 2018), heart (Na v 1.5) (Li Z. et al, 2021), and nerve (Na v 1.7) (Shen et al, 2019). All of these structures show the conservation of eukaryotic Na V architecture from arthropods to humans.…”

Section: Voltage-gated Sodium Channelsmentioning

confidence: 99%

“…It reveals that Na V contain four peripheral VSD (helices S1-S4) that are connected to the central, sodium-selective PD (helices S5-S6) by an amphipathic helix known as the S4-S5 linker (Figures 1A,B). These structures also provided some insights into the gating cycle of Na v by showing the position of the inactivation particle (IFM) and the conformation of the open activation gate, by way of an inactivation deficient mutant of Na v 1.5 (QQQ) (Jiang et al, 2021). Overall, these structures, in combination with functional data from similar constructs, highlighted the importance of distinct functional regions of the channel shown in Figure 1, including the VSD, PD, Elbow, S4-S5 Linker, IFM inactivation particle, activation gate, and selectivity filter.…”

Section: Voltage-gated Sodium Channelsmentioning

confidence: 99%

Fenestropathy of Voltage-Gated Sodium Channels

El-Din

Lenaeus

2022

Front. Pharmacol.

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Voltage-gated sodium channels (Nav) are responsible for the initiation and propagation of action potentials in excitable cells. From pain to heartbeat, these integral membrane proteins are the ignition stations for every sensation and action in human bodies. They are large (>200 kDa, 24 transmembrane helices) multi-domain proteins that couple changes in membrane voltage to the gating cycle of the sodium-selective pore. Nav mutations lead to a multitude of diseases - including chronic pain, cardiac arrhythmia, muscle illnesses, and seizure disorders - and a wide variety of currently used therapeutics block Nav. Despite this, the mechanisms of action of Nav blocking drugs are only modestly understood at this time and many questions remain to be answered regarding their state- and voltage-dependence, as well as the role of the hydrophobic membrane access pathways, or fenestrations, in drug ingress or egress. Nav fenestrations, which are pathways that connect the plasma membrane to the central cavity in the pore domain, were discovered through functional studies more than 40 years ago and once thought to be simple pathways. A variety of recent genetic, structural, and pharmacological data, however, shows that these fenestrations are actually key functional regions of Nav that modulate drug binding, lipid binding, and influence gating behaviors. We discovered that some of the disease mutations that cause arrhythmias alter amino acid residues that line the fenestrations of Nav1.5. This indicates that fenestrations may play a critical role in channel’s gating, and that individual genetic variation may also influence drug access through the fenestrations for resting/inactivated state block. In this review, we will discuss the channelopathies associated with these fenestrations, which we collectively name “Fenestropathy,” and how changes in the fenestrations associated with the opening of the intracellular gate could modulate the state-dependent ingress and egress of drugs binding in the central cavity of voltage gated sodium channels.

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Structural modeling of peptide toxin–ion channel interactions using RosettaDock

Mateos

Yarov‐Yarovoy

2023

Proteins

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Voltage-gated ion channels play essential physiological roles in action potential generation and propagation. Peptidic toxins from animal venoms target ion channels and provide useful scaffolds for the rational design of novel channel modulators with enhanced potency and subtype selectivity. Despite recent progress in obtaining experimental structures of peptide toxin-ion channel complexes, structural determination of peptide toxins bound to ion channels in physiologically important states remains challenging. Here we describe an application of RosettaDock approach to the structural modeling of peptide toxins interactions with ion channels. We tested this approach on 10 structures of peptide toxin-ion channel complexes and demonstrated that it can sample near-native structures in all tested cases. Our approach will be useful for improving the understanding of the molecular mechanism of natural peptide toxin modulation of ion channel gating and for the structural modeling of novel peptide-based ion channel modulators.ion channel, peptide toxin, protein-protein docking, protein-protein interactions, Rosetta, structural modeling | INTRODUCTIONVoltage-gated ion channels (VGICs) are transmembrane proteins that enable ions to permeate through the cell membrane in response to membrane depolarization. VGICs are involved in diverse and crucial

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Open-state structure and pore gating mechanism of the cardiac sodium channel

Cited by 70 publications

References 74 publications

Druggability of Voltage-Gated Sodium Channels—Exploring Old and New Drug Receptor Sites

Druggability of Voltage-Gated Sodium Channels—Exploring Old and New Drug Receptor Sites

Fenestropathy of Voltage-Gated Sodium Channels

Structural modeling of peptide toxin–ion channel interactions using RosettaDock

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