Key result
Fluorescence and NMR analyses revealed that the gating modifier toxin VSTx1 binds to the voltage-sensing domain of the KvAP channel in the depolarized 'up' conformation with a Kd of 1.5 μM.
Effect estimate: Kd 1.5 μM
This structural analysis reveals that the gating modifier toxin VSTx1 inhibits voltage-dependent K+ channels by stabilizing the voltage-sensing domain in its 'up' conformation.
Stabilizes Kv 'up' conformation in model channels; leaves open translation to human cardiac Kv function or antiarrhythmic potential.
Voltage-dependent K(+) (Kv) channels play crucial roles in nerve and muscle action potentials. Voltage-sensing domains (VSDs) of Kv channels sense changes in the transmembrane potential, regulating the K(+)-permeability across the membrane. Gating modifier toxins, which have been used for the functional analyses of Kv channels, inhibit Kv channels by binding to VSD. However, the structural basis for the inhibition remains elusive. Here, fluorescence and NMR analyses of the interaction between VSD derived from KvAP channel and its gating modifier toxin, VSTx1, indicate that VSTx1 recognizes VSD under depolarized condition. We identified the VSD-binding residues of VSTx1 and their proximal residues of VSD by the cross-saturation (CS) and amino acid selective CS experiments, which enabled to build a docking model of the complex. These results provide structural basis for the specific binding and inhibition of Kv channels by gating modifier toxins.
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Ozawa et al. (2015) studied this question. VSTx1 was evaluated on Binding affinity (Kd) and structural interaction between VSTx1 and VSD (Kd 1.5 μM). Fluorescence and NMR analyses revealed that the gating modifier toxin VSTx1 binds to the voltage-sensing domain of the KvAP channel in the depolarized 'up' conformation with a Kd of 1.5 μM.
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