Molecular interaction of δ-conopeptide EVIA with voltage-gated Na+ channels

Tietze, Daniel; Leipold, Enrico; Heimer, Pascal; Böhm, Miriam; Winschel, Wadim; Imhof, Diana; Heinemann, Stefan H.; Tietze, Alesia A.

doi:10.1016/j.bbagen.2016.06.013

Cited by 12 publications

(17 citation statements)

References 60 publications

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“…Native μ-SmIIIA occurs as the C-terminal acid, however, is usually used as an amide. 100 , 8 We used μ-SmIIIA as an amide for reasons of comparison because both structures were found to be identical. 30 # In general, the IC 50 values determined for the toxins ion channel blocking activity at the skeletal muscle Na V 1.4 expressed in Xenopus oocytes are given, with the exception of SmIIIA where only K D is available.…”

Section: Resultsmentioning

confidence: 99%

“…Conotoxins are neuropeptides from the venom of marine cone snails, which interact with a wide range of biological targets (e.g., ion channels, transmembrane receptors, and transporters) and hence are of pharmaceutical interest and of great potential as molecular probes to study the specific subtypes of ion channels and receptors. , Conotoxins consist of approximately 10–50 amino acid residues and are classified according to their cysteine patterns. , The typical CC–C–C–CC pattern defines the framework for conotoxins of the M-superfamily comprised by ψ-, μ-, and κM-conotoxins. ,, The family of the 27 currently known μ-conotoxins , selectively binds to the ion channel pore of the voltage-gated sodium channels, thus blocking the influx of sodium ions into the cell. Therefore, these peptides also gained interest as useful tools for research studies in electrophysiology. − μ-Conotoxins are cysteine-rich peptides consisting of 6 cysteines which can give rise to 15 conformational isomers of different disulfide connectivities in various combinations of disulfide bonds . However, the dominant isomer among them bears the disulfide linkage of C1–C4, C2–C5, and C3–C8, often referred to as the “native fold” .…”

Section: Introductionmentioning

confidence: 99%

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Insights into the Folding of Disulfide-Rich μ-Conotoxins

et al. 2018

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The study of protein conformations using molecular dynamics (MD) simulations has been in place for decades. A major contribution to the structural stability and native conformation of a protein is made by the primary sequence and disulfide bonds formed during the folding process. Here, we investigated μ-conotoxins GIIIA, KIIIA, PIIIA, SIIIA, and SmIIIA as model peptides possessing three disulfide bonds. Their NMR structures were used for MD simulations in a novel approach studying the conformations between the folded and the unfolded states by systematically breaking the distinct disulfide bonds and monitoring the conformational stability of the peptides. As an outcome, the use of a combination of the existing knowledge and results from the simulations to classify the studied peptides within the extreme models of disulfide folding pathways, namely the bovine pancreatic trypsin inhibitor pathway and the hirudin pathway, is demonstrated. Recommendations for the design and synthesis of cysteine-rich peptides with a reduced number of disulfide bonds conclude the study.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insights into the Folding of Disulfide-Rich μ-Conotoxins

et al. 2018

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“…Consequently, these peptides can serve as leads for drug and insecticide development whilst also being useful pharmacological tools for trapping VGICs in particular stages of the gating cycle. Numerous studies have been undertaken to understand the structure-activity relationships governing the interaction of these peptides with VGICs but the atomic details remain poorly understood, hindering rational engineering of more selective VGIC modulators 13 14 15 16 17 18 19 20 .…”

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confidence: 99%

Molecular basis of the interaction between gating modifier spider toxins and the voltage sensor of voltage-gated ion channels

Lau

King

Mobli

2016

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Voltage-sensor domains (VSDs) are modular transmembrane domains of voltage-gated ion channels that respond to changes in membrane potential by undergoing conformational changes that are coupled to gating of the ion-conducting pore. Most spider-venom peptides function as gating modifiers by binding to the VSDs of voltage-gated channels and trapping them in a closed or open state. To understand the molecular basis underlying this mode of action, we used nuclear magnetic resonance to delineate the atomic details of the interaction between the VSD of the voltage-gated potassium channel KvAP and the spider-venom peptide VSTx1. Our data reveal that the toxin interacts with residues in an aqueous cleft formed between the extracellular S1-S2 and S3-S4 loops of the VSD whilst maintaining lipid interactions in the gaps formed between the S1-S4 and S2-S3 helices. The resulting network of interactions increases the energetic barrier to the conformational changes required for channel gating, and we propose that this is the mechanism by which gating modifier toxins inhibit voltage-gated ion channels.

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“…In this interaction (Figure 3A), δ-conotoxins decreased the fast inactivation process by trapping S4, like the interaction mode of α-toxins from scorpions [154]. Recently, an interaction study made with δ-EVIA and Na v 1.7 showed that the δ-conotoxin additionally interacted with segment S5 of DI [155]. Identification of one Na + -current registered when normal kinetic inactivation of VGSCs is affected is shown in Figure 3E.…”

Section: Conotoxins Interacting With Voltage-gated Sodium Channelsmentioning

confidence: 86%

Structural and Functional Analyses of Cone Snail Toxins

2019

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Cone snails are marine gastropod mollusks with one of the most powerful venoms in nature. The toxins, named conotoxins, must act quickly on the cone snails´ prey due to the fact that snails are extremely slow, reducing their hunting capability. Therefore, the characteristics of conotoxins have become the object of investigation, and as a result medicines have been developed or are in the trialing process. Conotoxins interact with transmembrane proteins, showing specificity and potency. They target ion channels and ionotropic receptors with greater regularity, and when interaction occurs, there is immediate physiological decompensation. In this review we aimed to evaluate the structural features of conotoxins and the relationship with their target types.

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Molecular interaction of δ-conopeptide EVIA with voltage-gated Na+ channels

Cited by 12 publications

References 60 publications

Insights into the Folding of Disulfide-Rich μ-Conotoxins

Insights into the Folding of Disulfide-Rich μ-Conotoxins

Molecular basis of the interaction between gating modifier spider toxins and the voltage sensor of voltage-gated ion channels

Structural and Functional Analyses of Cone Snail Toxins

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