| Literature DB >> 31533989 |
Antonina A Berkut1, Anton O Chugunov1,2,3, Konstantin S Mineev1,3, Steve Peigneur4, Valentin M Tabakmakher1,5, Nikolay A Krylov1,2, Peter B Oparin1, Alyona F Lihonosova2, Ekaterina V Novikova1,3, Alexander S Arseniev1,3, Eugene V Grishin1, Jan Tytgat4, Roman G Efremov6,2,3, Alexander A Vassilevski7,3.
Abstract
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.Entities:
Keywords: alpha-hairpinin; hefutoxin; ion channel; molecular dynamics; neurotoxin; nuclear magnetic resonance (NMR); peptides; pore blocker; potassium channel; protein motif; protein structure
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Year: 2019 PMID： 31533989 PMCID： PMC6885618 DOI： 10.1074/jbc.RA119.010494
Source DB: PubMed Journal: J Biol Chem ISSN： 0021-9258 Impact factor: 5.157