scholarly journals Folding similarity of the outer pore region in prokaryotic and eukaryotic sodium channels revealed by docking of conotoxins GIIIA, PIIIA, and KIIIA in a NavAb-based model of Nav1.4

2014 ◽  
Vol 144 (3) ◽  
pp. 231-244 ◽  
Author(s):  
Viacheslav S. Korkosh ◽  
Boris S. Zhorov ◽  
Denis B. Tikhonov
Keyword(s):  
Experimental Data ◽  
Sodium Channels ◽  
Rational Design ◽  
Large Body ◽  
Homology Model ◽  
Selectivity Filter ◽  
Pore Region ◽  
X Ray ◽  
Voltage Gated Sodium Channels ◽  
Outer Pore

Voltage-gated sodium channels are targets for many drugs and toxins. However, the rational design of medically relevant channel modulators is hampered by the lack of x-ray structures of eukaryotic channels. Here, we used a homology model based on the x-ray structure of the NavAb prokaryotic sodium channel together with published experimental data to analyze interactions of the μ-conotoxins GIIIA, PIIIA, and KIIIA with the Nav1.4 eukaryotic channel. Using Monte Carlo energy minimizations and published experimentally defined pairwise contacts as distance constraints, we developed a model in which specific contacts between GIIIA and Nav1.4 were readily reproduced without deformation of the channel or toxin backbones. Computed energies of specific interactions between individual residues of GIIIA and the channel correlated with experimental estimates. The predicted complexes of PIIIA and KIIIA with Nav1.4 are consistent with a large body of experimental data. In particular, a model of Nav1.4 interactions with KIIIA and tetrodotoxin (TTX) indicated that TTX can pass between Nav1.4 and channel-bound KIIIA to reach its binding site at the selectivity filter. Our models also allowed us to explain experimental data that currently lack structural interpretations. For instance, consistent with the incomplete block observed with KIIIA and some GIIIA and PIIIA mutants, our computations predict an uninterrupted pathway for sodium ions between the extracellular space and the selectivity filter if at least one of the four outer carboxylates is not bound to the toxin. We found a good correlation between computational and experimental data on complete and incomplete channel block by native and mutant toxins. Thus, our study suggests similar folding of the outer pore region in eukaryotic and prokaryotic sodium channels.

Selectivity Filter Residues Contribute Unequally to Pore Stabilization in Voltage-Gated Sodium Channels†

Biochemistry ◽  
2005 ◽  
Vol 44 (42) ◽  
pp. 13874-13882 ◽  
Author(s):  
Karlheinz Hilber ◽  
Walter Sandtner ◽  
Touran Zarrabi ◽  
Eva Zebedin ◽  
Oliver Kudlacek ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Selectivity Filter ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals Tonic and Phasic Tetrodotoxin Block of Sodium Channels with Point Mutations in the Outer Pore Region

1999 ◽  
Vol 77 (1) ◽  
pp. 229-240 ◽  
Author(s):  
Anna Boccaccio ◽  
Oscar Moran ◽  
Keiji Imoto ◽  
Franco Conti
Keyword(s):  
Sodium Channels ◽  
Point Mutations ◽  
Pore Region ◽  
Outer Pore

scholarly journals Bases of Bacterial Sodium Channel Selectivity Among Organic Cations

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yibo Wang ◽  
Rocio K. Finol-Urdaneta ◽  
Van Anh Ngo ◽  
Robert J. French ◽  
Sergei Yu. Noskov
Keyword(s):  
Sodium Channels ◽  
Potential Of Mean Force ◽  
Selectivity Filter ◽  
Ion Permeation ◽  
Cation Selectivity ◽  
Functional Differences ◽  
Voltage Gated Sodium Channels ◽  
Channel Selectivity ◽  
Filter Size ◽  
Force Profiles

Abstract Hille’s (1971) seminal study of organic cation selectivity of eukaryotic voltage-gated sodium channels showed a sharp size cut-off for ion permeation, such that no ion possessing a methyl group was permeant. Using the prokaryotic channel, NaChBac, we found some similarity and two peculiar differences in the selectivity profiles for small polyatomic cations. First, we identified a diverse group of minimally permeant cations for wildtype NaChBac, ranging in sizes from ammonium to guanidinium and tetramethylammonium; and second, for both ammonium and hydrazinium, the charge-conserving selectivity filter mutation (E191D) yielded substantial increases in relative permeability (PX/PNa). The relative permeabilities varied inversely with relative Kd calculated from 1D Potential of Mean Force profiles (PMFs) for the single cations traversing the channel. Several of the cations bound more strongly than Na+, and hence appear to act as blockers, as well as charge carriers. Consistent with experimental observations, the E191D mutation had little impact on Na+ binding to the selectivity filter, but disrupted the binding of ammonium and hydrazinium, consequently facilitating ion permeation across the NaChBac-like filter. We concluded that for prokaryotic sodium channels, a fine balance among filter size, binding affinity, occupancy, and flexibility seems to contribute to observed functional differences.

scholarly journals Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants

2017 ◽  
Vol 149 (4) ◽  
pp. 465-481 ◽  
Author(s):  
Denis B. Tikhonov ◽  
Boris S. Zhorov
Keyword(s):  
Sodium Channel ◽  
Binding Sites ◽  
Local Anesthetics ◽  
Drug Binding ◽  
Selectivity Filter ◽  
Sodium Ion ◽  
X Ray ◽  
Common Drug ◽  
Voltage Gated Sodium Channels ◽  
Charged Group

Local anesthetics, antiarrhythmics, and anticonvulsants include both charged and electroneutral compounds that block voltage-gated sodium channels. Prior studies have revealed a common drug-binding region within the pore, but details about the binding sites and mechanism of block remain unclear. Here, we use the x-ray structure of a prokaryotic sodium channel, NavMs, to model a eukaryotic channel and dock representative ligands. These include lidocaine, QX-314, cocaine, quinidine, lamotrigine, carbamazepine (CMZ), phenytoin, lacosamide, sipatrigine, and bisphenol A. Preliminary calculations demonstrated that a sodium ion near the selectivity filter attracts electroneutral CMZ but repels cationic lidocaine. Therefore, we further docked electroneutral and cationic drugs with and without a sodium ion, respectively. In our models, all the drugs interact with a phenylalanine in helix IVS6. Electroneutral drugs trap a sodium ion in the proximity of the selectivity filter, and this same site attracts the charged group of cationic ligands. At this position, even small drugs can block the permeation pathway by an electrostatic or steric mechanism. Our study proposes a common pharmacophore for these diverse drugs. It includes a cationic moiety and an aromatic moiety, which are usually linked by four bonds.

scholarly journals Addition of K22 Converts Spider Venom Peptide Pme2a from an Activator to an Inhibitor of NaV1.7

Biomedicines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 37
Author(s):  
Kathleen Yin ◽  
Jennifer R. Deuis ◽  
Zoltan Dekan ◽  
Ai-Hua Jin ◽  
Paul F. Alewood ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Rational Design ◽  
Voltage Dependence ◽  
Spider Venom ◽  
Fast Inactivation ◽  
Peak Current ◽  
Native Peptide ◽  
Voltage Gated Sodium Channels ◽  
Nav Channels ◽  
And Shifts

Spider venom is a novel source of disulfide-rich peptides with potent and selective activity at voltage-gated sodium channels (NaV). Here, we describe the discovery of μ-theraphotoxin-Pme1a and μ/δ-theraphotoxin-Pme2a, two novel peptides from the venom of the Gooty Ornamental tarantula Poecilotheria metallica that modulate NaV channels. Pme1a is a 35 residue peptide that inhibits NaV1.7 peak current (IC50 334 ± 114 nM) and shifts the voltage dependence of activation to more depolarised membrane potentials (V1/2 activation: Δ = +11.6 mV). Pme2a is a 33 residue peptide that delays fast inactivation and inhibits NaV1.7 peak current (EC50 > 10 μM). Synthesis of a [+22K]Pme2a analogue increased potency at NaV1.7 (IC50 5.6 ± 1.1 μM) and removed the effect of the native peptide on fast inactivation, indicating that a lysine at position 22 (Pme2a numbering) is important for inhibitory activity. Results from this study may be used to guide the rational design of spider venom-derived peptides with improved potency and selectivity at NaV channels in the future.

scholarly journals Changes in Ion Selectivity Following the Asymmetrical Addition of Charge to the Selectivity Filter of Bacterial Sodium Channels

Entropy ◽  
2020 ◽  
Vol 22 (12) ◽  
pp. 1390
Author(s):  
Olena A. Fedorenko ◽  
Igor A. Khovanov ◽  
Stephen K. Roberts ◽  
Carlo Guardiani
Keyword(s):  
Molecular Dynamics ◽  
Sodium Channels ◽  
Ion Selectivity ◽  
Selectivity Filter ◽  
Na Channels ◽  
Site Specific ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Gating Charge ◽  
Dynamics Simulations

Voltage-gated sodium channels (NaVs) play fundamental roles in eukaryotes, but their exceptional size hinders their structural resolution. Bacterial NaVs are simplified homologues of their eukaryotic counterparts, but their use as models of eukaryotic Na+ channels is limited by their homotetrameric structure at odds with the asymmetric Selectivity Filter (SF) of eukaryotic NaVs. This work aims at mimicking the SF of eukaryotic NaVs by engineering radial asymmetry into the SF of bacterial channels. This goal was pursued with two approaches: the co-expression of different monomers of the NaChBac bacterial channel to induce the random assembly of heterotetramers, and the concatenation of four bacterial monomers to form a concatemer that can be targeted by site-specific mutagenesis. Patch-clamp measurements and Molecular Dynamics simulations showed that an additional gating charge in the SF leads to a significant increase in Na+ and a modest increase in the Ca2+ conductance in the NavMs concatemer in agreement with the behavior of the population of random heterotetramers with the highest proportion of channels with charge −5e. We thus showed that charge, despite being important, is not the only determinant of conduction and selectivity, and we created new tools extending the use of bacterial channels as models of eukaryotic counterparts.

Protonation state of the selectivity filter of bacterial voltage‐gated sodium channels is modulated by ions

2019 ◽  
Vol 88 (3) ◽  
pp. 527-539 ◽  
Author(s):  
Ana Damjanovic ◽  
Ada Y. Chen ◽  
Robert L. Rosenberg ◽  
Daniel R. Roe ◽  
Xiongwu Wu ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Selectivity Filter ◽  
Protonation State ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals Brevetoxin and Conotoxin Interactions with Single-Domain Voltage-Gated Sodium Channels from a Diatom and Coccolithophore

Marine Drugs ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. 140
Author(s):  
Ping Yates ◽  
Julie A. Koester ◽  
Alison R. Taylor
Keyword(s):  
Ion Channels ◽  
Sodium Channels ◽  
Single Domain ◽  
Marine Diatom ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
State Dependent ◽  
Steady State Inactivation ◽  
Outer Pore ◽  
Voltage Gated Ion Channels

The recently characterized single-domain voltage-gated ion channels from eukaryotic protists (EukCats) provide an array of novel channel proteins upon which to test the pharmacology of both clinically and environmentally relevant marine toxins. Here, we examined the effects of the hydrophilic µ-CTx PIIIA and the lipophilic brevetoxins PbTx-2 and PbTx-3 on heterologously expressed EukCat ion channels from a marine diatom and coccolithophore. Surprisingly, none of the toxins inhibited the peak currents evoked by the two EukCats tested. The lack of homology in the outer pore elements of the channel may disrupt the binding of µ-CTx PIIIA, while major structural differences between mammalian sodium channels and the C-terminal domains of the EukCats may diminish interactions with the brevetoxins. However, all three toxins produced significant negative shifts in the voltage dependence of activation and steady state inactivation, suggesting alternative and state-dependent binding conformations that potentially lead to changes in the excitability of the phytoplankton themselves.

Evidence for ordered Fe3Ni

1987 ◽  
Vol 45 ◽  
pp. 216-217
Author(s):  
K.B. Reuter ◽  
D.B. Williams ◽  
J.I. Goldstein
Keyword(s):  
Experimental Data ◽  
Martensitic Transformation ◽  
Electron Diffraction ◽  
Room Temperature ◽  
Direct Evidence ◽  
Transformation Product ◽  
Iron Meteorites ◽  
X Ray ◽  
Ni Content ◽  
Temperature Transformation

In the Fe-Ni system, although ordered FeNi and ordered Ni3Fe are experimentally well established, direct evidence for ordered Fe3Ni is unconvincing. Little experimental data for Fe3Ni exists because diffusion is sluggish at temperatures below 400°C and because alloys containing less than 29 wt% Ni undergo a martensitic transformation at room temperature. Fe-Ni phases in iron meteorites were examined in this study because iron meteorites have cooled at slow rates of about 10°C/106 years, allowing phase transformations below 400°C to occur. One low temperature transformation product, called clear taenite 2 (CT2), was of particular interest because it contains less than 30 wtZ Ni and is not martensitic. Because CT2 is only a few microns in size, the structure and Ni content were determined through electron diffraction and x-ray microanalysis. A Philips EM400T operated at 120 kV, equipped with a Tracor Northern 2000 multichannel analyzer, was used.

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