Solution structure of the potassium channel inhibitor agitoxin 2: Caliper for probing channel geometry

Andrzej M. Krezel, Chandrasekhar Kasibhatla, Patricia Hidalgo, Roderick Mackinnon, Gerhard Wagner

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

The structure of the potassium channel blocker agitoxin 2 was solved by solution NMR methods. The structure consists of a triple‐stranded antiparallel β‐sheet and a single helix covering one face of the β‐sheet. The cysteine side chains connecting the β‐sheet and the helix form the core of the molecule. One edge of the β‐sheet and the adjacent face of the helix form the interface with the Shaker K+ channel. The fold of agitoxin is homologous to the previously determined folds of scorpion venom toxins. However, agitoxin 2 differs significantly from the other channel blockers in the specificity of its interactions. This study was thus focused on a precise characterization of the surface residues at the face of the protein interacting with the Shaker K+ channel. The rigid toxin molecule can be used to estimate dimensions of the potassium channel. Surface‐exposed residues, Arg24, Lys27, and Arg31 of the β‐sheet, have been identified from mutagenesis studies as functionally important for blocking the Shaker K+ channel. The sequential and spatial locations of Arg24 and Arg31 are not conserved among the homologous toxins. Knowledge on the details of the channel‐binding sites of agitoxin 2 formed a basis for site‐directed mutagenesis studies of the toxin and the K+ channel sequences. Observed interactions between mutated toxin and channel are being used to elucidate the channel structure and mechanisms of channel‐toxin interactions.

Original languageEnglish
Pages (from-to)1478-1489
Number of pages12
JournalProtein Science
Volume4
Issue number8
DOIs
StatePublished - Aug 1995
Externally publishedYes

Keywords

  • K channel
  • NMR
  • agitoxin
  • protein
  • scorpion toxin

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