Molecular modeling of interactions of agitoxin 2 with Kv1.3 voltage-gated potassium channel

The Kv1.3 voltage-gated potassium channel is involved in a number of processes in excitable and nonexcitable cells: maintenance of resting membrane potential, signal transduction, apoptosis, regulation of cell volume, activation and proliferation of white blood cells. Blocking this channel is an effective approach for the treatment of autoimmune, oncological, chronic inflammatory, and metabolic diseases. The most prospective blockers of Kv1.3 are toxins isolated from the venom of scorpions. Knowledge of the molecular aspects of binding of peptide blockers with the channel is an important condition for the creation of highly effective and selective ligands. In the present work, a complex of hybrid channel KcsA-Kv1.3 with agitoxin 2 was built using homology modeling and molecular dynamics simulation. Analysis of formed contacts allowed us to reveal a complete pattern of interactions and to identify key residues that are responsible for the toxin binding affinity. Results of computational experiment are consistent with the experimental data and important for drug development. © 2017, Allerton Press, Inc.