A C-terminally amidated analogue of ShK is a potent and selective blocker of the voltage-gated potassium channel Kv1.3

Michael William Pennington, M Harunur Rashid, Rajeev B Tajhya, Christine Beeton, Serdar Kuyucak, Raymond Stanley Norton

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

Abstract

ShK, a 35-residue peptide from a sea anemone, is a potent blocker of potassium channels. Here we describe a new ShK analogue with an additional C-terminus Lys residue and amide. ShK-K-amide is a potent blocker of Kv1.3 and, in contrast to ShK and ShK-amide, is selective for Kv1.3. To understand this selectivity, we created complexes of ShK-K-amide with Kv1.3 and Kv1.1 using docking and molecular dynamics simulations, then performed umbrella sampling simulations to construct the potential of mean force of the ligand and calculate the corresponding binding free energy for the most stable configuration. The results agree well with experimental data. (c) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Original languageEnglish
Pages (from-to)3996 - 4001
Number of pages6
JournalFEBS Letters
Volume586
Issue number22
DOIs
Publication statusPublished - 2012

Cite this