One sting from the “mankiller” scorpion, Androctonus australis, can be enough to kill a full-grown human. The scorpion delivers a neurotoxin that alters the flow of sodium ions into nerve cells, leaving them permanently stuck in the “on” position and leading to muscle paralysis and in some cases, death by heart or respiratory failure.

Androctonus venom does its lethal work by preventing voltage-gated sodium (Nav) channels -- which are critical for mediating signals in our brain and muscle tissue – from resetting. Unable to transmit information, disrupted Nav channels can lead to an array of conditions including epilepsy, migraines, cardiac arrhythmias, muscle paralysis and pain syndromes. As a result, medicines that target Nav channel dysfunction could potentially treat such conditions.

Some scorpion toxins modulate Nav channels with extremely high potency and specificity — which piqued the curiosity of researchers working to develop Nav-targeting therapies. One challenge in developing Nav-targeted therapies has been visualizing how natural toxins interact with Nav channel receptors.  Advances in the imaging technology cryogenic electron microscopy (cryo-EM), which captures 3D protein structures in their native state within frozen protein solutions, has allowed scientists to gain a high-resolution picture of the interaction between toxins and receptors.

Two studies recently published in Science and Cell used cryo-EM to uncover the structural basis of how toxins from Androctonus as well as the Peruvian green velvet tarantula bind to Nav channels. These findings provide some of the first high-resolution snapshots of how these toxins potently and selectively modulate Nav channel activity. Cryo-EM, along with other experimental techniques, revealed that Protoxin-II from tarantula venom binds to voltage-sensor domain II (VSD2) of the Nav channel and blocks activation through electrostatic repulsion. Similarly, the lethal AaH2 scorpion toxin wedges itself into VSD4 of the Nav channel, and functions essentially as a stopper to trap it in a deactivated state.

Together, these data provide a much more comprehensive picture of how Nav channels work and could ultimately inform the development of highly targeted Nav channel modulators for therapeutic use.

You can learn more about this research by visiting the Science and Cell journal websites.