Open conformation of hERG channel turrets revealed by a specific scorpion toxin BmKKx2

You Tian Hu, Jun Hu, Tian Li, Jing Jing Wei, Jing Feng, Yi Mei Du, Zhi Jian Cao, Wen Xin Li, Ying Liang Wu

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Background: The human ether-a-go-go-related gene potassium channel (hERG) has an unusual long turret, whose role in recognizing scorpion toxins remains controversial. Here, BmKKx2, the first specific blocker of hERG channel derived from scorpion Mesobuthus martensii, was identified and the turret role of hERG channel was re-investigated using BmKKx2 as a molecular probe.Results: BmKKx2 was found to block hERG channel with an IC50 of 6.7 ± 1.7 nM and share similar functional surface with the known hERG channel inhibitor BeKm-1. The alanine-scanning mutagenesis data indicate that different residue substitutions on hERG channel by alanine decreased the affinities of toxin BmKKx2 by about 10-fold compared with that of wild-type hERG channel, which reveals that channel turrets play a secondary role in toxin binding. Different from channel turret, the pore region of hERG channel was found to exert the conserved and essential function for toxin binding because the mutant hERG-S631A channel remarkably decreased toxin BmKKx2 affinity by about 104-fold.Conclusions: Our results not only revealed that channel turrets of hERG channel formed an open conformation in scorpion toxin binding, but also enriched the diversity of structure-function relationships among the different potassium channel turrets.

Original languageEnglish
Article number18
JournalCell and Bioscience
Volume4
Issue number1
DOIs
StatePublished - Apr 11 2014

Keywords

  • BmKKx2
  • Molecular mechanism
  • Pore region
  • Scorpion toxin
  • Turret
  • hERG channel

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