title: Positive selection-guided mutational analysis revealing two key functional sites of scorpion ERG K(+) channel toxins.
abstract: Scorpion γ-KTx toxins are important molecular tools for studying physiological and pharmacological functions of human ether-á-go-go related gene (hERG) K(+) channels. To pinpoint functional residues of this class of toxins involved in channel binding, we employed a combined approach that integrates evolutionary information and site-directed mutagenesis. Among three positively selected sites (PSSs) identified here, two (Gln18 and Met35) were found to be associated with the toxin's function because their changes significantly decreased the potency of ErgTx1 (also called CnErg1) on hERG1 channel. On the contrary, no potency alteration was observed at the third PSS (Ala42) when the mutation was introduced, which could be due to its location far from the functional surface of the toxin. Our strategy will accelerate the research of structure-function relationship of scorpion K(+) channel toxins.
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, Beijing 100101, PR China.
authors.forename: Xueli
authors.initials: X
authors.lastname: Wang
authors.forename: Juana Maria
authors.initials: JM
authors.lastname: Jimenez-Vargas
authors.forename: Chenqi
authors.initials: C
authors.lastname: Xu
authors.forename: Lourival D
authors.initials: LD
authors.lastname: Possani
authors.forename: Shunyi
authors.initials: S
authors.lastname: Zhu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004252:DNA Mutational Analysis; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005973:Glutamine / Q000235:genetics; D006801:Humans; D008715:Methionine / Q000235:genetics; D008969:Molecular Sequence Data; D012604:Scorpion Venoms / Q000235:genetics* / Q000494:pharmacology*; D012641:Selection, Genetic; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D012604:Scorpion Venoms; C118951:ergotoxin, Centruroides noxius; D005973:Glutamine; D008715:Methionine