Structural determinants of scorpion toxin affinity: The charybdotoxin (α-KTX) family of K+-channel blocking peptides

Tenenholz, T.C.; Klenk, K.C.; Matteson, D R; Blaustein, M. P.; Weber, David J.

doi:10.1007/bfb0035552

Cited by 32 publications

(30 citation statements)

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“…The best studied scorpion toxins with respect to interacting surfaces are the K + channel-specific toxins [9,13,15,16,19]. Less information is available for those specific for Na + channels.…”

Section: Discussionmentioning

confidence: 99%

“…The last of these is not trivial, as the huge variability of these peptides, estimated to be of the order of 100 000 in scorpion venom alone, and of which only about 0.2% have been identified, leaves a wide open field for research [4,5,8]. Several recent articles and reviews have reported on the structural and functional aspects of these peptides [3,[8][9][10][11][12][13][14][15][16][17][18]. Most dealt with scorpion toxins as ion-channels blockers or modifiers of their function.…”

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confidence: 99%

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NMR solution structure of Cn12, a novel peptide from the Mexican scorpion Centruroides noxius with a typical β‐toxin sequence but with α‐like physiological activity

Rı́o-Portilla

Hernández-Marín

Pimienta

et al. 2004

European Journal of Biochemistry

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Cn12 isolated from the venom of the scorpion Centruroides noxius has 67 amino-acid residues, closely packed with four disulfide bridges. Its primary structure and disulfide bridges were determined. Cn12 is not lethal to mammals and arthropods in vivo at doses up to 100 lg per animal. Its 3D structure was determined by proton NMR using 850 distance constraints, 36 / angles derived from 36 coupling constants obtained by two different methods, and 22 hydrogen bonds. The overall structure has a two and half turn a-helix (residues 24-32), three strands of antiparallel b-sheet (residues 2-4, 37-40 and 45-48), and a type II turn (residues 41-44). The amino-acid sequence of Cn12 resembles the b scorpion toxin class, although patch-clamp experiments showed the induction of supplementary slow inactivation of Na + channels in F-11 cells (mouse neuroblastoma N18TG-2 · rat DRG2), which means that it behaves more like an a scorpion toxin. This behaviour prompted us to analyse Na + channel binding sites using information from 112 Na + channel gene clones available in the literature, focusing on the extracytoplasmic loops of the S5-S6 transmembrane segments of domain I and the S3-S4 segments of domain IV, sites considered to be responsible for binding a scorpion toxins.Keywords: Centruroides noxius; NMR structure; patchclamp; scorpion toxin; sodium channel.Scorpion toxins are relatively short peptides with a variable length of amino acids, showing characteristic 3D folding comprised of an a-helix and three segments of antiparallel b-sheet structure, stabilized by several disulfide bridges [1][2][3][4][5]. Their known physiological role is to block or modify ion-channel function, causing impairment of cellular communication, which leads to the depolarization of excitable membranes and might cause death of animals stung by scorpions [6,7].There are several reasons why the molecular basis of toxin specificity and molecular mechanism of action continue to be of scientific interest: (a) to study ion channels, the target molecules of most known scorpion toxins, in order to understand their molecular structure and function, thus learning more about cellular excitability; (b) to understand the toxic effects of scorpion venoms, a prerequisite for the development of more effective and safer antidotes and/or vaccines; (c) to find toxins specific for invertebrate organisms with a view to developing biodegradable drugs for pest control; (d) to discover other possible unknown target molecules for which peptides were evolved in the venom of scorpions. The last of these is not trivial, as the huge variability of these peptides, estimated to be of the order of 100 000 in scorpion venom alone, and of which only about 0.2% have been identified, leaves a wide open field for research [4,5,8]. Several recent articles and reviews have reported on the structural and functional aspects of these peptides [3,[8][9][10][11][12][13][14][15][16][17][18]. Most dealt with scorpion toxins as ion-channels blockers or modifiers of their function. However, the st...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

NMR solution structure of Cn12, a novel peptide from the Mexican scorpion Centruroides noxius with a typical β‐toxin sequence but with α‐like physiological activity

Rı́o-Portilla

Hernández-Marín

Pimienta

et al. 2004

European Journal of Biochemistry

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“…Except for a few toxin peptides with eight cysteines, most α-KTx, β-KTx, and γ-KTx toxins have six cysteines and exhibit cross-linking with three disulfide bridges (CX 2−6 CX 3 CX 5−10 CX 3−12 CX 1 C). Many of toxin peptides are effective inhibitors of Kv1.3 channel and have proven to be powerful tools for testing the pharmacological, physiological, and structural characteristics of Kv1.3 channel [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

ImKTx1, a new Kv1.3 channel blocker with a unique primary structure

Chen

Han

et al. 2011

J Biochem & Molecular Tox

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Toxins from the venoms of scorpion, snake, and spider are valuable tools to probe the structure-function relationship of ion channels. In this investigation, a new toxin gene encoding the peptide ImKTx1 was isolated from the venom gland of the scorpion Isometrus maculates by constructing cDNA library method, and the recombinant ImKTx1 peptide was characterized physiologically. The mature peptide of ImKTx1 has 39 amino acid residues including six cross-linked cysteines. The electrophysiological experiments showed that the recombinant ImKTx1 peptide had a pharmacological profile where it inhibited Kv1.3 channel currents with IC(50) of 1.70 n± 1.35 µM, whereas 10 µM rImKTx1 peptide inhibited about 40% Kv1.1 and 42% Kv1.2 channel currents, respectively. In addition, 10 µM rImKTx1 had no effect on the Nav1.2 and Nav1.4 channel currents. Multiple sequence alignments showed that ImKTx1 had no homologous toxin peptide, but it was similar with Ca(2+) channel toxins from scorpion and spider in the arrangement of cysteine residues. These results indicate that ImKTx1 is a new Kv1.3 channel blocker with a unique primary structure. Our results indicate the diversity of K(+) channel toxins from scorpion venoms and also provide a new molecular template targeting Kv1.3 channel.

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“…data]. Similarly, a peptide toxin from the scorpion, Tityus serrulatus (TsTX-K·), is also thought to be selective for K v 1-type channels [107], and TsTX-K· blocks native K + currents in GFL neurons and those from oocytes expressing SqK v 1.1A with a similar affinity [94]. Interestingly, in both cases the block is highly pH dependent, being almost completely abolished at low pH.…”

Section: Functional Properties Of Sqk V 11a and Comparison With Natimentioning

confidence: 99%

Identified Ion Channels in the Squid Nervous System

Rosenthal

Gilly²

2003

Neurosignals

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Our modern understanding of channels as discrete voltage-sensitive and ion-selective entities comes largely from a series of classical studies using the squid giant axon. This system has also been critical for understanding how transporters and synaptic transmission operate. This review outlines attempts to assign molecular identities to the extensively studied physiological properties of this system. As it turns out, this is no simple task. Molecular candidates for voltage-gated Na⁺, K⁺, and Ca²⁺ channels, as well as ion transporters have been isolated from the squid nervous system. Both physiological and molecular approaches have been used to equate these cloned gene products with their native counterparts. In the case of the delayed rectifier K⁺ conductance, the most thoroughly studied example, two major issues further complicate the equation. First, the ability of K⁺ channel monomers to form heteromultimers with unique properties must be considered. Second, squid K⁺ channel mRNAs are extensively edited, a process that can generate a wide variety of channel proteins from a common gene. The giant axon system is beginning to play an important role in understanding the biological relevance of this latter process.

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Structural determinants of scorpion toxin affinity: The charybdotoxin (α-KTX) family of K+-channel blocking peptides

Cited by 32 publications

References 123 publications

NMR solution structure of Cn12, a novel peptide from the Mexican scorpion Centruroides noxius with a typical β‐toxin sequence but with α‐like physiological activity

NMR solution structure of Cn12, a novel peptide from the Mexican scorpion Centruroides noxius with a typical β‐toxin sequence but with α‐like physiological activity

ImKTx1, a new Kv1.3 channel blocker with a unique primary structure

Identified Ion Channels in the Squid Nervous System

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