1. Characterization and Chemical Synthesis of Cm39 (α-KTx 4.8): A Scorpion Toxin That Inhibits Voltage-Gated K + Channel K V 1.2 and Small- and Intermediate-Conductance Ca 2+ -Activated K + Channels K Ca 2.2 and K Ca 3.1.
- Author
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Naseem, Muhammad Umair, Gurrola-Briones, Georgina, Romero-Imbachi, Margarita R., Borrego, Jesus, Carcamo-Noriega, Edson, Beltrán-Vidal, José, Zamudio, Fernando Z., Shakeel, Kashmala, Possani, Lourival Domingos, and Panyi, Gyorgy
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SCORPION venom , *TOXINS , *CHEMICAL synthesis , *AMINO acid residues , *AMINO acid sequence , *SCORPIONS , *PEPTIDES - Abstract
A novel peptide, Cm39, was identified in the venom of the scorpion Centruroides margaritatus. Its primary structure was determined. It consists of 37 amino acid residues with a MW of 3980.2 Da. The full chemical synthesis and proper folding of Cm39 was obtained. Based on amino acid sequence alignment with different K+ channel inhibitor scorpion toxin (KTx) families and phylogenetic analysis, Cm39 belongs to the α-KTx 4 family and was registered with the systematic number of α-KTx 4.8. Synthetic Cm39 inhibits the voltage-gated K+ channel hKV1.2 with high affinity (Kd = 65 nM). The conductance–voltage relationship of KV1.2 was not altered in the presence of Cm39, and the analysis of the toxin binding kinetics was consistent with a bimolecular interaction between the peptide and the channel; therefore, the pore blocking mechanism is proposed for the toxin–channel interaction. Cm39 also inhibits the Ca2+-activated KCa2.2 and KCa3.1 channels, with Kd = 502 nM, and Kd = 58 nM, respectively. However, the peptide does not inhibit hKV1.1, hKV1.3, hKV1.4, hKV1.5, hKV1.6, hKV11.1, mKCa1.1 K+ channels or the hNaV1.5 and hNaV1.4 Na+ channels at 1 μM concentrations. Understanding the unusual selectivity profile of Cm39 motivates further experiments to reveal novel interactions with the vestibule of toxin-sensitive channels. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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