Mesomartoxin, a new Kv1.2-selective scorpion toxin interacting with the channel selectivity filter.

Wang X1, Umetsu Y2, Gao B1, Ohki S2, Zhu S3.

Biochem Pharmacol. 2015 Jan 15;93(2):232-9. .

Abstract

Venom-derived neurotoxins are ideal probes for the investigation of structure-function relationship of ion channels and promising scaffolds for the design of ion channel-targeted drug leads as well. 

The discovery of highly selective toxins against a specific channel subtype facilitates the development of drugs with reduced side effects. 

Here, we describe the systemic characterization of a new scorpion short-chain K(+) channel blocker from Mesobuthus

 martensii, termed mesomartoxin (MMTX).

 MMTX is synthesized as a precursor comprising a signal

 peptide and a mature peptide of 29 residues. 

Nuclear magnetic resonance analysis confirmed that

 recombinant MMTX adopts a typical cysteine-stabilized α-

helical and β-sheet fold. 

Electrophysiological experiments showed that MMTX exhibits

 high affinity for the Drosophila Shaker K(+) channel but

 differential selectivity on different members of the rat

 voltage-gated K(+) channel (Kv) family, with nanomolar 

affinity (IC50=15.6nM) for rKv1.2, micromolar affinity for 

rKv1.3 (IC50=12.5μM) and no activity on rKv1.1 at >50μM. 

Site-directed mutagenesis of the channel pore identified a key site located on the selectivity filter of the pore, which is directly implicated in toxin binding and controls target's selectivity of the toxin. 

Given a key role of Kv1.2 in epilepsy, MMTXmight serve as a potential drug lead for the disease.