title: Mesomartoxin, a new K(v)1.2-selective scorpion toxin interacting with the channel selectivity filter.
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=15.6 nM) for rKv1.2, micromolar affinity for rKv1.3 (IC50=12.5 μM) and no activity on rKv1.1 at >50 μM. 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, MMTX might serve as a potential drug lead for the disease.
authors.affiliation: Group of Animal Innate Immunity, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101 Beijing, China.
authors.forename: Xueli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center for Nano Materials and Technology (CNMT), Japan Advanced Institute of Science and Technology (JAIST), 1-1 Asahidai, Nomi, Ishikawa 923-1292, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Umetsu
authors.affiliation: Group of Animal Innate Immunity, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101 Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Center for Nano Materials and Technology (CNMT), Japan Advanced Institute of Science and Technology (JAIST), 1-1 Asahidai, Nomi, Ishikawa 923-1292, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ohki
authors.affiliation: Group of Animal Innate Immunity, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101 Beijing, China. Electronic address: Zhusy@ioz.ac.cn.
authors.forename: Shunyi
authors.initials: S
authors.lastname: Zhu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D051663:Kv1.2 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D012604:Scorpion Venoms / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D051663:Kv1.2 Potassium Channel; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms
keywords: Mesobuthus martensii; Selectivity filter; Site-directed mutagenesis; Voltage-gated K(+) channel