Mechanism of Calcium Permeation in a Glutamate Receptor Ion Channel

Schackert, Florian Karl; Biedermann, Johann; Abdolvand, Saeid; Minniberger, Sonja; Song, Chen; Plested, Andrew J.R.; Carloni, Paolo; Sun, Han

doi:10.1021/acs.jcim.2c01494

Cited by 14 publications

(11 citation statements)

References 73 publications

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“…Within this condition, the carboxylic groups of aspartic acids are saturated by calcium ions, and new ions injected in the pore push an internal calcium ion to exit, reminding the knock-off mechanism also proposed very recently for other calcium channels ( Schackert et al, 2023 ). In particular, the residue at position P2 has the highest residence time for calcium, providing a bridge between position P1 and P3, Figure 5 .…”

Section: Discussionmentioning

confidence: 60%

Electrophysiological properties and structural prediction of the SARS-CoV-2 viroprotein E

Cubisino,

Milenkovic,

Conti-Nibali

et al. 2024

Front. Mol. Biosci.

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COVID-19, the infectious disease caused by the most recently discovered coronavirus SARS- CoV-2, has caused millions of sick people and thousands of deaths all over the world. The viral positive-sense single-stranded RNA encodes 31 proteins among which the spike (S) is undoubtedly the best known. Recently, protein E has been reputed as a potential pharmacological target as well. It is essential for the assembly and release of the virions in the cell. Literature describes protein E as a voltage-dependent channel with preference towards monovalent cations whose intracellular expression, though, alters Ca2+ homeostasis and promotes the activation of the proinflammatory cascades. Due to the extremely high sequence identity of SARS-CoV-2 protein E (E-2) with the previously characterized E-1 (i.e., protein E from SARS-CoV) many data obtained for E-1 were simply adapted to the other. Recent solid state NMR structure revealed that the transmembrane domain (TMD) of E-2 self-assembles into a homo-pentamer, albeit the oligomeric status has not been validated with the full-length protein. Prompted by the lack of a common agreement on the proper structural and functional features of E-2, we investigated the specific mechanism/s of pore-gating and the detailed molecular structure of the most cryptic protein of SARS-CoV-2 by means of MD simulations of the E-2 structure and by expressing, refolding and analyzing the electrophysiological activity of the transmembrane moiety of the protein E-2, in its full length. Our results show a clear agreement between experimental and predictive studies and foresee a mechanism of activity based on Ca2+ affinity.

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Section: Discussionmentioning

confidence: 60%

Electrophysiological properties and structural prediction of the SARS-CoV-2 viroprotein E

Cubisino,

Milenkovic,

Conti-Nibali

et al. 2024

Front. Mol. Biosci.

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“…A potential of 10 mV Å –1 was set. Not too dissimilar potentials have been used in other setups, such as the computational electrophysiology simulations. − Here, 3 μs were simulated with and without the electric field, using a simpler one-dimensional CV space (see Figure S14a in Supporting Information).…”

Section: Methodsmentioning

confidence: 99%

Physical Chemistry of Chloroquine Permeation through the Cell Membrane with Atomistic Detail

Paulikat,

Piccini,

Ippoliti

et al. 2023

J. Chem. Inf. Model.

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We provide a molecular-level description of the thermodynamics and mechanistic aspects of drug permeation through the cell membrane. As a case study, we considered the antimalaria FDA approved drug chloroquine. Molecular dynamics simulations of the molecule (in its neutral and protonated form) were performed in the presence of different lipid bilayers, with the aim of uncovering key aspects of the permeation process, a fundamental step for the drug’s action. Free energy values obtained by well-tempered metadynamics simulations suggest that the neutral form is the only permeating protomer, consistent with experimental data. H-bond interactions of the drug with water molecules and membrane headgroups play a crucial role for permeation. The presence of the transmembrane potential, investigated here for the first time in a drug permeation study, does not qualitatively affect these conclusions.

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“…The CHARMM36m force field was used for the protein, ions other than Ca 2+ , and the lipids [36] . For the Ca 2+ ions, the multi-site model developed by Zhang et al was used, which has recently been shown by us and other groups to reliably model Ca 2+ currents in a range of ion channels [37][38][39][40][41] Hydrogen mass re-partitioning (HMR) of the system was used in the simulations with Na + ions such that 4-fs time steps could be employed [42] . However, 4-fs time steps are incompatible with the multi-site Ca 2+ model, and consequently, a standard 2-fs time step was used in all simulations with Ca 2+ , retaining HMR for consistency.…”

Section: Methodsmentioning

confidence: 99%

Characterisation of ligand gating, ion conduction and the ion selectivity mechanism in the endo-lysosomal ion channel hTPC2

Şahin,

Zachariae

2023

Preprint

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Two pore channels (TPCs) are two-fold symmetric endo-lysosomal cation channels forming important drug targets especially for antiviral drugs. They are activated by calcium, ligand binding, and membrane voltage, and to date, are the only ion channels shown to alter their ion selectivity depending on the type of bound ligand. However, despite their importance in the field, ligand activation of TPCs and the molecular mechanisms underlying their ion selectivity are still poorly understood. Here, we set out to elucidate the mechanistic basis for the ion selectivity of human TPC2 (hTPC2) and the molecular mechanism of ligand-induced channel activation by the lipid PI(3,5)P2. We performed all-atom in silico electrophysiology simulations to study Na+and Ca2+permeation across hTPC2 in real-time and to investigate the conformational changes induced by the presence or absence of bound PI(3,5)P2. Our findings reveal that hTPC2 adopts distinct structures depending on the presence of PI(3,5)P2and elucidate the conformational transition pathways between these structures. Additionally, we examined the permeation mechanism, solvation states, and binding sites of ions during ion permeation through the pore. Our simulations reproduce the experimental observation that hTPC2 is more selective for Na+over Ca2+ions in the presence of PI(3,5)P2and explain the mechanism of this ion selectivity. They highlight the importance of specific ion binding sites at the luminal channel entrance, the selectivity filter, and the central channel cavity for ion conduction, enabling a distant knock-on mechanism for efficient permeation of Na+ions.

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Mechanism of Calcium Permeation in a Glutamate Receptor Ion Channel

Cited by 14 publications

References 73 publications

Electrophysiological properties and structural prediction of the SARS-CoV-2 viroprotein E

Electrophysiological properties and structural prediction of the SARS-CoV-2 viroprotein E

Physical Chemistry of Chloroquine Permeation through the Cell Membrane with Atomistic Detail

Characterisation of ligand gating, ion conduction and the ion selectivity mechanism in the endo-lysosomal ion channel hTPC2

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