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A C‐terminally amidated analogue of ShK is a potent and selective blocker of the voltage‐gated potassium channel Kv1.3
Author(s) -
Pennington Michael W.,
Harunur Rashid M.,
Tajhya Rajeev B.,
Beeton Christine,
Kuyucak Serdar,
Norton Raymond S.
Publication year - 2012
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2012.09.038
Subject(s) - potassium channel , potassium channel blocker , chemistry , potassium , potassium channel opener , voltage gated potassium channel , voltage gated ion channel , channel (broadcasting) , pharmacology , biochemistry , biophysics , ion channel , receptor , medicine , biology , computer science , organic chemistry , telecommunications
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.