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Solution structure of a K⁺-channel blocker from the scorpion Tityus cambridgei

¹ Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
² Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan
³ Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan

Reprint requests to: Chinpan Chen, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; e-mail: bmchinp{at}ccvax.sinica.edu.tw; fax: 886-2-2788-7641 or Shih-Hsiung Wu, Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; e-mail: shwu{at}gate.sinica.edu.tw; fax: 886-2-2653-9142.

A new K⁺-channel blocking peptide identified from the scorpion venom of Tityus cambridgei (Tc1) is composed of 23 amino acid residues linked with three disulfide bridges. Tc1 is the shortest known toxin from scorpion venom that recognizes the Shaker B K⁺ channels and the voltage-dependent K⁺ channels in the brain. Synthetic Tc1 was produced using solid-phase synthesis, and its activity was found to be the same as that of native Tc1. The pairings of three disulfide bridges in the synthetic Tc1 were identified by NMR experiments. The NMR solution structures of Tc1 were determined by simulated annealing and energy-minimization calculations using the X-PLOR program. The results showed that Tc1 contains an -helix and a 3₁₀-helix at N-terminal Gly⁴–Lys¹⁰ and a double-stranded ß-sheet at Gly¹³–Ile¹⁶ and Arg¹⁹–Tyr²³, with a type I` ß-turn at Asn¹⁷–Gly¹⁸. Superposition of each structure with the best structure yielded an average root mean square deviation of 0.26 ± 0.05 Å for the backbone atoms and of 1.40 ± 0.23 Å for heavy atoms in residues 2 to 23. The three-dimensional structure of Tc1 was compared with two structurally and functionally related scorpion toxins, charybdotoxin (ChTx) and noxiustoxin (NTx). We concluded that the C-terminal structure is the most important region for the blocking activity of voltage-gated (Kv-type) channels for scorpion K⁺-channel blockers. We also found that some of the residues in the larger scorpion K⁺-channel blockers (31 to 40 amino acids) are not involved in K⁺-channel blocking activity.

Keywords: Scorpion venom; -KTx; K+-channel blocker; NMR; structure

Abbreviations: Tc1, a new scorpion toxin from Tityus cambridgei • NTx, noxiustoxin • ChTx, charybdotoxin • KTx, kaliotoxin • MgTx, margatoxin • IbTx, iberiotoxin • TsTx-K, tityustoxin K- • BKca, large-conductance calcium-activated potassium channel • Kv, Shaker-related voltage-gated potassium channel • CD, circular dichroism • NOE, nuclear Overhauser enhancement • DQF-COSY, double-quantum-filtered scalar-correlated spectroscopy • TOCSY, total correlation spectroscopy • RMSD, root mean square deviation • CSI, chemical shift index

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