Selective block of human Kv1.1 channels and an epilepsy-associated gain-of-function mutation by AETX-K peptide.

ABSTRACT: Dysfunction of the human voltage-gated K⁺ channel Kv1.1 has been associated with epilepsy, multiple sclerosis, episodic ataxia, myokymia, and cardiorespiratory dysregulation. We report here that AETX-K, a sea anemone type I (SAK1) peptide toxin we isolated from a phage display library, blocks Kv1.1 with high affinity (K_i  ~ 1.6 pM) and notable specificity, inhibiting other Kv channels we tested a million-fold less well. Nuclear magnetic resonance (NMR) was employed both to determine the three-dimensional structure of AETX-K, showing it to employ a classic SAK1 scaffold while exhibiting a unique electrostatic potential surface, and to visualize AETX-K bound to the Kv1.1 pore domain embedded in lipoprotein nanodiscs. Study of Kv1.1 in Xenopus oocytes with AETX-K and poi

SUBMITTER: Zhao R 

PROVIDER: S-EPMC10754259 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature