Abstract
Thermally processed Buthus martensii Karsch scorpions are a traditional Chinese medical material for treating various diseases. However, their pharmacological foundation remains unclear. Here, a new degraded peptide of scorpion toxin was identified in Chinese scorpion medicinal material by proteomics. It was named BmK86-P1 and has six conserved cysteine residues. Homology modeling and circular dichroism spectra experiments revealed that BmK86-P1 not only contained representative disulfide bond-stabilized α-helical and β-sheet motifs but also showed remarkable stability at test temperatures from 20–95 °C. Electrophysiology experiments indicated that BmK86-P1 was a highly potent and selective inhibitor of the hKv1.2 channel with IC50 values of 28.5 ± 6.3 nM. Structural and functional dissection revealed that two residues of BmK86-P1 (i.e., Lys19 and Ile21) were the key residues that interacted with the hKv1.2 channel. In addition, channel chimeras and mutagenesis experiments revealed that three amino acids (i.e., Gln357, Val381 and Thr383) of the hKv1.2 channel were responsible for BmK86-P1 selectivity. This research uncovered a new bioactive peptide from traditional Chinese scorpion medicinal material that has desirable thermostability and Kv1.2 channel-specific activity, which strongly suggests that thermally processed scorpions are novel peptide resources for new drug discovery for the Kv1.2 channel-related ataxia and epilepsy diseases.
Highlights
Processed Buthus martensii Karsch scorpions are traditional Chinese medical material for treating many diseases, such as chronic pain, rheumatoid arthritis, and apoplexy [1]
Mass spectrometrybased proteomics has revealed that there is a large number of wild-type peptides and novel degraded peptides that have the potential to act on potassium channels in processed scorpion medicinal material [2], and some of these classical neurotoxins and degraded peptides have been shown to be potent potassium channel inhibitors, such as BmKKx2, BmKTX, BmKcug2 and BmKcug2-P1 [2,3]
This study found the novel Kv1.2-selective peptide BmK86-P1 from the scorpion medicinal material and clarified the mechanism by which BmK86-P1 interacted with the human Kv1.2 channel, which was helpful for unveiling the medicinal active ingredients of the traditional Chinese scorpion medicinal material
Summary
Processed Buthus martensii Karsch scorpions are traditional Chinese medical material for treating many diseases, such as chronic pain, rheumatoid arthritis, and apoplexy [1]. We identified a novel potassium channel-inhibiting BmK86 peptide analog, BmK86-P1, from the scorpion medicinal material by proteomics. Pharmacological experiments showed that BmK86-P1 selectively exhibited a high affinity for the human Kv1.2 channel with IC50 values of 28.5 ± 6.3 nM. The site-directed mutagenesis and channel chimera experiments illustrated the key amino acids of BmK86-P1 interacting with the human Kv1.2 channel and the channel critical residues responsible for the BmK86-P1 toxin selectivity. This study found the novel Kv1.2-selective peptide BmK86-P1 from the scorpion medicinal material and clarified the mechanism by which BmK86-P1 interacted with the human Kv1.2 channel, which was helpful for unveiling the medicinal active ingredients of the traditional Chinese scorpion medicinal material
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