Key result
The 1H-NMR three-dimensional solution structure of native ergtoxin (CnErg1) was solved, revealing two important amino acid residue clusters involved in surface contact with the ERG K+ channel.
The determination of the 3D structure of CnErg1 provides insights into the structural features required for its interaction with ERG K+ channels.
Structural insights into ergtoxin-ERG contacts may inform channel modulator design; leaves open therapeutic translation in cardiac electrophysiology.
The gamma-KTx-type scorpion toxins specific for K+ channels were found to interact with ERG channels on the turret region, while alpha-KTx3.2 Agitoxin-2 binds to the pore region of the Shaker K+ channel, and alpha-KTx5.3 BmP05 binds to the intermediate region of the small-conductance calcium-activated K-channel (SK(Ca)). In order to explore the critical residues for gamma-KTx binding, we determined the NMR structure of native gamma-KTx1.1 (CnErg1), a 42 amino acid residues scorpion toxin isolated from the venom of the Mexican scorpion Centruroïdes noxius Hoffmann, and we used computational evolutionary trace (ET) analysis to predict possible structural and functional features of interacting surfaces. The 1H-NMR three-dimensional solution structure of native ergtoxin (CnErg1) was solved using a total of 452 distance constraints, 13 3J(NH-Halpha) and 10 hydrogen bonds. The structure is characterized by 2 segments of alpha-helices and a triple-stranded antiparallel beta-sheet stabilized by 4 disulfide bridges. The ET and structural analysis provided indication of the presence of two important amino acid residue clusters, one hydrophobic and the other hydrophilic, that should be involved in the surface contact between the toxin and the channel. Some features of the proposed interacting surface are discussed.
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Frénal et al. (2004) studied this question. CnErg1 (gamma-KTx1.1) was evaluated on NMR structure and interacting surfaces. The 1H-NMR three-dimensional solution structure of native ergtoxin (CnErg1) was solved, revealing two important amino acid residue clusters involved in surface contact with the ERG K+ channel.
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