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Regular version of the site

Article

K⁠V1.2 channel-specific blocker from Mesobuthus eupeus scorpion venom: Structural basis of selectivity.

Neuropharmacology. 2018. Vol. 143. P. 228-238.
Kuzmenkov A., Nekrasova⁠ O., Peigneur⁠ S., Tabakmakher⁠ V., Gigolaev⁠ A., Fradkov⁠ A., Kudryashova⁠ K., Chugunov A., Efremov R., Tytgat⁠ J., Feofanov⁠ A., Vassilevski A.

Scorpion venom is an unmatched source of selective high-affinity ligands of potassium channels. There is a high
demand for such compounds to identify and manipulate the activity of particular channel isoforms. The objective
of this study was to obtain and characterize a specific ligand of voltage-gated potassium channel KV1.2. As a
result, we report the remarkable selectivity of the peptide MeKTx11-1 (α-KTx 1.16) from Mesobuthus eupeus
scorpion venom to this channel isoform. MeKTx11-1 is a high-affinity blocker of KV1.2 (IC50 ∼0.2 nM), while its
activity against KV1.1, KV1.3, and KV1.6 is 10 000, 330 and 45 000 fold lower, respectively, as measured using
the voltage-clamp technique on mammalian channels expressed in Xenopus oocytes. Two substitutions, G9V and
P37S, convert MeKTx11-1 to its natural analog MeKTx11-3 (α-KTx 1.17) having 15 times lower activity and
reduced selectivity to KV1.2. We produced MeKTx11-1 and MeKTx11-3 as well as their mutants MeKTx11-
1(G9V) and MeKTx11-1(P37S) recombinantly and demonstrated that point mutations provide an intermediate
effect on selectivity. Key structural elements that explain MeKTx11-1 specificity were identified by molecular
modeling of the toxin–channel complexes. Confirming our molecular modeling predictions, site-directed transfer
of these elements from the pore region of KV1.2 to KV1.3 resulted in the enhanced sensitivity of mutant KV1.3
channels to MeKTx11-1. We conclude that MeKTx11-1 may be used as a selective tool in neurobiology.