The primary structure of noxiustoxin: A K+ channel blocking peptide, purified from the venom of the scorpion Centruroides noxius Hoffmann

Possani, Lourival D.; Martin, Brian M.; Svendsen, Ib

doi:10.1007/bf02907789

Cited by 135 publications

(6 citation statements)

References 19 publications

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“…The sequence analysis and phylogenetic tree reveal that the seven CboK peptide toxins bear a great deal of resemblance to the α-KTxs that block voltage-gated potassium (Kv1) channels. Based on the similarity index of CboK peptides with other α-KTxs and the literature available for the activity of closely related peptides [ 36 , 37 ], Kv1.1, Kv1.2, and Kv1.3 K + channels were selected as the potential target of CboK peptides. Macroscopic Kv1.1 and Kv1.2 currents were measured in transiently transfected CHO cells.…”

Section: Resultsmentioning

confidence: 99%

Of Seven New K+ Channel Inhibitor Peptides of Centruroides bonito, α-KTx 2.24 Has a Picomolar Affinity for Kv1.2

Shakeel

Olamendi-Portugal

Naseem

et al. 2023

Toxins

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Seven new peptides denominated CboK1 to CboK7 were isolated from the venom of the Mexican scorpion Centruroides bonito and their primary structures were determined. The molecular weights ranged between 3760.4 Da and 4357.9 Da, containing 32 to 39 amino acid residues with three pu-tative disulfide bridges. The comparison of amino acid sequences with known potassium scorpion toxins (KTx) and phylogenetic analysis revealed that CboK1 (α-KTx 10.5) and CboK2 (α-KTx 10.6) belong to the α-KTx 10.x subfamily, whereas CboK3 (α-KTx 2.22), CboK4 (α-KTx 2.23), CboK6 (α-KTx 2.21), and CboK7 (α-KTx 2.24) bear > 95% amino acid similarity with members of the α-KTx 2.x subfamily, and CboK5 is identical to Ce3 toxin (α-KTx 2.10). Electrophysiological assays demonstrated that except CboK1, all six other peptides blocked the Kv1.2 channel with Kd values in the picomolar range (24–763 pM) and inhibited the Kv1.3 channel with comparatively less po-tency (Kd values between 20–171 nM). CboK3 and CboK4 inhibited less than 10% and CboK7 in-hibited about 42% of Kv1.1 currents at 100 nM concentration. Among all, CboK7 showed out-standing affinity for Kv1.2 (Kd = 24 pM), as well as high selectivity over Kv1.3 (850-fold) and Kv1.1 (~6000-fold). These characteristics of CboK7 may provide a framework for developing tools to treat Kv1.2-related channelopathies.

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Section: Resultsmentioning

confidence: 99%

Of Seven New K+ Channel Inhibitor Peptides of Centruroides bonito, α-KTx 2.24 Has a Picomolar Affinity for Kv1.2

Shakeel

Olamendi-Portugal

Naseem

et al. 2023

Toxins

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“…Les canaux potassium sont ubiquistes : ils se rencontrent chez tous les êtres vivants même chez les plus simples (Jan & Jan, 1997). La première toxine de venin de scorpion active sur les canaux potassium, la noxiustoxine, a été isolée par Possani et al (1982) à partir du venin du scorpion mexicain Centruroides noxius. Leur rôle essentiel étant de contrôler le potentiel de membrane cellulaire, les canaux potassium sont impliqués dans des fonctions variées, comme par exemple la libération d'un neurotransmetteur (Sitges et al, 1986).…”

Section: Les Toxines Courtes Actives Sur Les Canaux Potassiumunclassified

“…Elles peuvent agir sur des canaux K v ou K Ca . Historiquement, elles ont été les premières à être découvertes dans les venins de scorpions (noxiustoxine, Possani et al, 1982 ;Sitges et al, 1986). La molécule de référence est la charybdotoxine (CTX), du venin du scorpion paléotropical Leiurus quinquestriatus, et cette molécule qui a pu être synthétisée est utilisée pour la classification de cette catégorie de toxines en sous-familles, en fonction du degré d'homologie de la séquence analysée avec celle de la charybdotoxine (Legros & Goyffon, 2010) (figure 2).…”

Section: Les Toxines Courtes Actives Sur Les Canaux Potassiumunclassified

Relations entre la fonction venimeuse et la fonction immunitaire innée

Goyffon

Saul

Faure

2015

Biologie Aujourd'hui

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Venomous function is investigated in relation to innate immune function in two cases selected from scorpion venom and serpent venom. In the first case, structural analysis of scorpion toxins and defensins reveals a close interrelation between both functions (toxic and innate immune system function). In the second case, structural and functional studies of natural inhibitors of toxic snake venom phospholipases A2 reveal homology with components of the innate immune system, leading to a similar conclusion. Although there is a clear functional distinction between neurotoxins, which act by targeting membrane ion channels, and the circulating defensins which protect the organism from pathogens, the scorpion short toxins and defensins share a common protein folding scaffold with a conserved cysteine-stabilized alpha-beta motif of three disulfide bridges linking a short alpha helix and an antiparallel beta sheet. Genomic analysis suggests that these proteins share a common ancestor (long venom toxins were separated from an early gene family which gave rise to separate short toxin and defensin families). Furthermore, a scorpion toxin has been experimentally synthetized from an insect defensin, and an antibacterial scorpion peptide, androctonin (whose structure is similar to that of a cone snail venom toxin), was shown to have a similar high affinity for the postsynaptic acetylcholine receptor of Torpedo sp. Natural inhibitors of phospholipase A2 found in the blood of snakes are associated with the resistance of venomous snakes to their own highly neurotoxic venom proteins. Three classes of phospholipases A2 inhibitors (PLI-α, PLI-β, PLI-γ) have been identified. These inhibitors display diverse structural motifs related to innate immune proteins including carbohydrate recognition domains (CRD), leucine rich repeat domains (found in Toll-like receptors) and three finger domains, which clearly differentiate them from components of the adaptive immune system. Thus, in structure, function and phylogeny, venomous function in both vertebrates and invertebrates are clearly interrelated with innate immune function.

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“…when venom preparation obtained from the Mexican scorpion Centruroides noxius was applied to a giant squid axon, while monitoring by means of voltage-clamp [25]. The single constituent responsible for the observed activity was Noxiustoxin (NTX), a 39 AA peptide purified from homogenized crude venom extract, and separated by Sephadex G-50 chromatography, followed by ion-exchange [26]. Although isolated and purified, the multi-faceted potential of the toxin was not yet realized.…”

Section: The Use Of Scorpion Toxins To Investigate Potassium Channelsmentioning

confidence: 99%

“…This resulted in the production of native-like material and truncated versions of NTX [65]. The biologically active, synthetic peptide was desirable for two reasons, (i) a large number of scorpions (~1000) would need to be milked in order to obtain quantities of material suitable for pharmacological experimentation (1 mg), as NTX represents only a fraction of the total protein (~1%) in the crude venom extract [26], and (ii) truncated versions of NTX do not occur naturally [65]. Noxiustoxin and the truncated terminal peptide segments were assayed and their pharmacological activity compared.…”

Section: Synthetic Toxin Productionmentioning

confidence: 99%

Scorpion Toxins Specific for Potassium (K+) Channels: A Historical Overview of Peptide Bioengineering

Bergeron

Bingham

2012

Toxins

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Scorpion toxins have been central to the investigation and understanding of the physiological role of potassium (K+) channels and their expansive function in membrane biophysics. As highly specific probes, toxins have revealed a great deal about channel structure and the correlation between mutations, altered regulation and a number of human pathologies. Radio- and fluorescently-labeled toxin isoforms have contributed to localization studies of channel subtypes in expressing cells, and have been further used in competitive displacement assays for the identification of additional novel ligands for use in research and medicine. Chimeric toxins have been designed from multiple peptide scaffolds to probe channel isoform specificity, while advanced epitope chimerization has aided in the development of novel molecular therapeutics. Peptide backbone cyclization has been utilized to enhance therapeutic efficiency by augmenting serum stability and toxin half-life in vivo as a number of K+-channel isoforms have been identified with essential roles in disease states ranging from HIV, T-cell mediated autoimmune disease and hypertension to various cardiac arrhythmias and Malaria. Bioengineered scorpion toxins have been monumental to the evolution of channel science, and are now serving as templates for the development of invaluable experimental molecular therapeutics.

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The primary structure of noxiustoxin: A K+ channel blocking peptide, purified from the venom of the scorpion Centruroides noxius Hoffmann

Cited by 135 publications

References 19 publications

Of Seven New K+ Channel Inhibitor Peptides of Centruroides bonito, α-KTx 2.24 Has a Picomolar Affinity for Kv1.2

Of Seven New K+ Channel Inhibitor Peptides of Centruroides bonito, α-KTx 2.24 Has a Picomolar Affinity for Kv1.2

Relations entre la fonction venimeuse et la fonction immunitaire innée

Scorpion Toxins Specific for Potassium (K+) Channels: A Historical Overview of Peptide Bioengineering

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