Research Article

Structural basis for the modulation of voltage-gated sodium channels by animal toxins

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Science  26 Jul 2018:
eaau2596
DOI: 10.1126/science.aau2596

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Abstract

Animal toxins that modulate the activity of Nav channels are broadly divided into two categories—pore blockers and gating modifiers. The pore blockers tetrodotoxin (TTX) and saxitoxin (STX) are responsible for pufferfish and shellfish poisoning in humans, respectively. Here we present structures of the insect Nav channel NavPaS bound to a gating modifier toxin Dc1a at 2.8 Å and in the presence of TTX or STX at 2.6 Å and 3.2 Å resolution, respectively. Dc1a inserts into the cleft between VSDII and the pore of NavPaS, making key contacts with both domains. The structures with bound TTX or STX reveal the molecular details for the specific blockade of Na+ access to the selectivity filter from the extracellular side by these guanidinium toxins. The structures shed light on structure-based development of Nav channel drugs.

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