Protein surface topography as a tool to enhance the selective activity of a potassium channel blocker

Tk-hefu is an artificial peptide designed based on the α-hairpinin scaffold, which selectively blocks voltage-gated potassium channels Kv1.3. Here we present its spatial structure resolved by NMR spectroscopy and analyze its interaction with channels using computer modeling. We apply protein surface...

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Bibliographic Details
Published in:The Journal of biological chemistry 2019-11, Vol.294 (48), p.18349-18359
Main Authors: Berkut, Antonina A., Chugunov, Anton O., Mineev, Konstantin S., Peigneur, Steve, Tabakmakher, Valentin M., Krylov, Nikolay A., Oparin, Peter B., Lihonosova, Alyona F., Novikova, Ekaterina V., Arseniev, Alexander S., Grishin, Eugene V., Tytgat, Jan, Efremov, Roman G., Vassilevski, Alexander A.
Format: Article
Language:English
Subjects:
alpha-hairpinin
Amino Acid Sequence
Animals
Computational Biology
hefutoxin
Humans
ion channel
Kv1.3 Potassium Channel - chemistry
Kv1.3 Potassium Channel - metabolism
Ligands
Magnetic Resonance Spectroscopy
Mass Spectrometry
molecular dynamics
Molecular Dynamics Simulation
Mutation
neurotoxin
nuclear magnetic resonance (NMR)
peptides
Peptides - chemistry
Peptides - genetics
Peptides - metabolism
pore blocker
potassium channel
Potassium Channel Blockers - chemistry
Potassium Channel Blockers - metabolism
Protein Binding
Protein Conformation
protein motif
protein structure
Proteins - chemistry
Proteins - metabolism
Surface Properties
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Description
Summary:Tk-hefu is an artificial peptide designed based on the α-hairpinin scaffold, which selectively blocks voltage-gated potassium channels Kv1.3. Here we present its spatial structure resolved by NMR spectroscopy and analyze its interaction with channels using computer modeling. We apply protein surface topography to suggest mutations and increase Tk-hefu affinity to the Kv1.3 channel isoform. We redesign the functional surface of Tk-hefu to better match the respective surface of the channel pore vestibule. The resulting peptide Tk-hefu-2 retains Kv1.3 selectivity and displays ∼15 times greater activity compared with Tk-hefu. We verify the mode of Tk-hefu-2 binding to the channel outer vestibule experimentally by site-directed mutagenesis. We argue that scaffold engineering aided by protein surface topography represents a reliable tool for design and optimization of specific ion channel ligands.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.RA119.010494