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Research article

Cobatoxin 1 from Centruroides noxius scorpion venom: chemical synthesis, three-dimensional structure in solution, pharmacology and docking on K+ channels

Besma JOUIROU, Amor MOSBAH, Violeta VISAN, Stephan GRISSMER, Sarrah M'BAREK, Ziad FAJLOUN, Jurphaas VAN RIETSCHOTEN, Christiane DEVAUX, Hervé ROCHAT, Guy LIPPENS, Mohamed EL AYEB, Michel DE WAARD, Kamel MABROUK, Jean-Marc SABATIER
Biochemical Journal Jan 01, 2004, 377 (1) 37-49; DOI: 10.1042/bj20030977
Besma JOUIROU
Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS UMR 6560, Bd Pierre Dramard, 13916 Marseille Cedex 20, FranceLaboratoire des Venins et Toxines, Institut Pasteur de Tunis, Tunis-Belvédère, Tunisia
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Amor MOSBAH
Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS UMR 6560, Bd Pierre Dramard, 13916 Marseille Cedex 20, France
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Violeta VISAN
Universität Ulm, Albert Einstein-Allee 11, D-89081 Ulm, Germany
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Stephan GRISSMER
Universität Ulm, Albert Einstein-Allee 11, D-89081 Ulm, Germany
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Sarrah M'BAREK
Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS UMR 6560, Bd Pierre Dramard, 13916 Marseille Cedex 20, France
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Ziad FAJLOUN
Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS UMR 6560, Bd Pierre Dramard, 13916 Marseille Cedex 20, France
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Jurphaas VAN RIETSCHOTEN
Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS UMR 6560, Bd Pierre Dramard, 13916 Marseille Cedex 20, France
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Christiane DEVAUX
Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS UMR 6560, Bd Pierre Dramard, 13916 Marseille Cedex 20, France
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Hervé ROCHAT
Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS UMR 6560, Bd Pierre Dramard, 13916 Marseille Cedex 20, France
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Guy LIPPENS
CNRS UMR 8525, Institut Pasteur de Lille, 1 rue du Professeur Calmette BP447, 59021, Lille Cedex, France
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Mohamed EL AYEB
Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS UMR 6560, Bd Pierre Dramard, 13916 Marseille Cedex 20, FranceLaboratoire des Venins et Toxines, Institut Pasteur de Tunis, Tunis-Belvédère, Tunisia
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Michel DE WAARD
Inserm EMI 9931, CEA, IFR 27, DRDC, Canaux Ioniques et Signalisation, 17 rue des Martyrs, 38054 Grenoble Cedex 09, France
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Kamel MABROUK
Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS UMR 6560, Bd Pierre Dramard, 13916 Marseille Cedex 20, France
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Jean-Marc SABATIER
Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS UMR 6560, Bd Pierre Dramard, 13916 Marseille Cedex 20, France
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Abstract

CoTX1 (cobatoxin 1) is a 32-residue toxin with three disulphide bridges that has been isolated from the venom of the Mexican scorpion Centruroides noxius Hoffmann. Here we report the chemical synthesis, disulphide bridge organization, 3-D (three-dimensional) solution structure determination, pharmacology on K+ channel subtypes (voltage-gated and Ca2+-activated) and docking-simulation experiments. An enzyme-based cleavage of the synthetic folded/oxidized CoTX1 indicated half-cystine pairs between Cys3-Cys22, Cys8-Cys27 and Cys12-Cys29. The 3-D structure of CoTX1 (solved by 1H-NMR) showed that it folds according to the common α/β scaffold of scorpion toxins. In vivo, CoTX1 was lethal after intracerebroventricular injection to mice (LD50 value of 0.5 µg/mouse). In vitro, CoTX1 tested on cells expressing various voltage-gated or Ca2+-activated (IKCa1) K+ channels showed potent inhibition of currents from rat Kv1.2 (Kd value of 27 nM). CoTX1 also weakly competed with 125I-labelled apamin for binding to SKCa channels (small-conductance Ca2+-activated K+ channels) on rat brain synaptosomes (IC50 value of 7.2 µM). The 3-D structure of CoTX1 was used in docking experiments which suggests a key role of Arg6 or Lys10, Arg14, Arg18, Lys21 (dyad), Ile23, Asn24, Lys28 and Tyr30 (dyad) residues of CoTX1 in its interaction with the rat Kv1.2 channel. In addition, a [Pro7,Gln9]-CoTX1 analogue (ACoTX1) was synthesized. The two residue replacements were selected aiming to restore the RPCQ motif in order to increase peptide affinity towards SKCa channels, and to alter the CoTX1 dipole moment such that it is expected to decrease peptide activity on Kv channels. Unexpectedly, ACoTX1 exhibited an activity similar to that of CoTX1 towards SKCa channels, while it was markedly more potent on IKCa1 and several voltage-gated K+ channels.

  • chemical synthesis
  • cobatoxin 1
  • docking simulation
  • K+ channel
  • scorpion toxin
  • three-dimensional structure

Footnotes

  • ↵1 These authors contributed equally to this work.

  • Abbreviations used: CoTX1, cobatoxin 1; ACoTX1, synthetic structural cobatoxin 1 analogue with Pro and Gln at positions 7 and 9, respectively; NOE, nuclear Overhauser effect; DQF-COSY, double-quantum-filtered correlation spectroscopy; DIANA, distance geometry algorithm for NMR; CNS, crystallography and NMR system; HN, amide proton; Fmoc, Nα-(9-fluorenyl)methyloxycarbonyl; SKCa channel, small-conductance Ca2+-activated K+ channel; IKCa1 channel, intermediate-conductance Ca2+-activated K+ channel; hIKCa1, human IKCa1; Kv channel, mammalian voltage-gated K+ channel; Shaker B channel, insect voltage-gated K+ channel; Shaker B Δ44 channel, Shaker B channel formed by α subunits truncated at their N-terminal extremity (region 1–44); TFA, trifluoroacetic acid; MALDI-TOF, matrix-assisted laser-desorption ionization–time-of-flight; 3-D, three-dimensional; r.m.s.d., root mean square deviation.

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January 2004

Volume: 377 Issue: 1

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Cobatoxin 1 from Centruroides noxius scorpion venom: chemical synthesis, three-dimensional structure in solution, pharmacology and docking on K+ channels
Besma JOUIROU, Amor MOSBAH, Violeta VISAN, Stephan GRISSMER, Sarrah M'BAREK, Ziad FAJLOUN, Jurphaas VAN RIETSCHOTEN, Christiane DEVAUX, Hervé ROCHAT, Guy LIPPENS, Mohamed EL AYEB, Michel DE WAARD, Kamel MABROUK, Jean-Marc SABATIER
Biochemical Journal Jan 2004, 377 (1) 37-49; DOI: 10.1042/bj20030977
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Cobatoxin 1 from Centruroides noxius scorpion venom: chemical synthesis, three-dimensional structure in solution, pharmacology and docking on K+ channels
Besma JOUIROU, Amor MOSBAH, Violeta VISAN, Stephan GRISSMER, Sarrah M'BAREK, Ziad FAJLOUN, Jurphaas VAN RIETSCHOTEN, Christiane DEVAUX, Hervé ROCHAT, Guy LIPPENS, Mohamed EL AYEB, Michel DE WAARD, Kamel MABROUK, Jean-Marc SABATIER
Biochemical Journal Jan 2004, 377 (1) 37-49; DOI: 10.1042/bj20030977

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Keywords

chemical synthesis
cobatoxin 1
docking simulation
K+ channel
scorpion toxin
three-dimensional structure

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