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Structure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin
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Structure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin
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Structure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin
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Journal Article
Structure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin
2023
Overview
The sodium channel Na
V
1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na
V
1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human Na
V
1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of Na
V
1.6 inhibition by the blocker. The apo-form structure reveals two potential Na
+
binding sites within the selectivity filter, suggesting a possible mechanism for Na
+
selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na
+
binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into Na
V
1.6 structure, ion conductance, and inhibition.
Na
V
1.6 channel plays a critical role in neuronal excitability. Here, authors present human Na
V
1.6 structures in apo and 4,9-anhydro-tetrodotoxin bound forms, which reveal molecular mechanisms of Na
V
1.6 Na
+
conductance and inhibition by the blocker.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 82/80
/ 82/83
/ 9/74
/ Epilepsy
/ Humanities and Social Sciences
/ Science
/ Sodium
/ Sodium channels (voltage-gated)
/ Toxins
