TY - JOUR
T1 - A C-terminally amidated analogue of ShK is a potent and selective blocker of the voltage-gated potassium channel Kv1.3
AU - Pennington, Michael William
AU - Rashid, M Harunur
AU - Tajhya, Rajeev B
AU - Beeton, Christine
AU - Kuyucak, Serdar
AU - Norton, Raymond Stanley
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
UR - http://www.elsevier.com/locate/febslet
U2 - 10.1016/j.febslet.2012.09.038
DO - 10.1016/j.febslet.2012.09.038
M3 - Article
SN - 0014-5793
VL - 586
SP - 3996
EP - 4001
JO - FEBS Letters
JF - FEBS Letters
IS - 22
ER -