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

• Published in: Science (American Association for the Advancement of Science) Vol. 362; no. 6412
• Main Authors: Shen, Huaizong, Li, Zhangqiang, Jiang, Yan, Pan, Xiaojing, Wu, Jianping, Cristofori-Armstrong, Ben, Smith, Jennifer J, Chin, Yanni K Y, Lei, Jianlin, Zhou, Qiang, King, Glenn F, Yan, Nieng
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 19-10-2018
• Subjects: Amino Acid Sequence; Animals; Arrhythmia; Binding sites; Biochemical analysis; Blattella germanica; Cations; Cell membranes; Channel gating; Channel opening; Chronic pain; Cryoelectron Microscopy; Deserts; Diguetia canities; Docking; Domains; Drug development; Drug discovery; Electric contacts; Electric potential; Electron microscopy; Electronegativity; Electrostatic properties; Epilepsy; Homology; Insect Proteins - antagonists & inhibitors; Insect Proteins - chemistry; Insect Proteins - ultrastructure; Insects; Inserts; Ion Channel Gating - drug effects; Ion channels; Literary Devices; Modulation; Muscles; Mutation; Neurotoxins; Pain; Periplaneta; Periplaneta americana; Poisoning; Predators; Prey; Protein Domains; Residues; Saxitoxin; Saxitoxin - chemistry; Selectivity; Shellfish; Sodium; Sodium channels (voltage-gated); Sodium chloride; Spider Venoms - chemistry; Tetrodotoxin; Tetrodotoxin - chemistry; Toxins; Venom; Voltage-Gated Sodium Channel Blockers - chemistry; Voltage-Gated Sodium Channels - chemistry; Voltage-Gated Sodium Channels - ultrastructure
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aau2596

Animal toxins that modulate the activity of voltage-gated sodium (Na
) channels are broadly divided into two categories-pore blockers and gating modifiers. The pore blockers tetrodotoxin (TTX) and saxitoxin (STX) are responsible for puffer fish and shellfish poisoning in humans, respectively. Here, we present structures of the insect Na
channel Na
PaS bound to a gating modifier toxin Dc1a at 2.8 angstrom-resolution and in the presence of TTX or STX at 2.6-Å and 3.2-Å resolution, respectively. Dc1a inserts into the cleft between VSD
and the pore of Na
PaS, 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 Na
channel drugs.