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.
Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Algorithms
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Amides / chemistry
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Animals
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Binding Sites
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Binding, Competitive
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cells, Cultured
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Cnidarian Venoms / chemistry
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Cnidarian Venoms / metabolism
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Cnidarian Venoms / pharmacology*
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Dose-Response Relationship, Drug
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Humans
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Ion Channel Gating / drug effects*
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Ion Channel Gating / genetics
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Ion Channel Gating / physiology
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Kv1.1 Potassium Channel / genetics
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Kv1.1 Potassium Channel / metabolism
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Kv1.1 Potassium Channel / physiology
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Kv1.3 Potassium Channel / genetics
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Kv1.3 Potassium Channel / metabolism
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Kv1.3 Potassium Channel / physiology*
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Mice
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Models, Molecular
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Molecular Dynamics Simulation
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Patch-Clamp Techniques
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Potassium Channel Blockers / chemistry
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Potassium Channel Blockers / metabolism
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Potassium Channel Blockers / pharmacology*
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Protein Binding
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Protein Structure, Tertiary
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
Substances
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Amides
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Cnidarian Venoms
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Kv1.3 Potassium Channel
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Potassium Channel Blockers
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ShK neurotoxin
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Kv1.1 Potassium Channel