8GZ2

Cryo-EM structure of human NaV1.6/beta1/beta2-4,9-anhydro-tetrodotoxin

Summary for 8GZ2

• Entry DOI: 10.2210/pdb8gz2/pdb
• EMDB information: 34388
• Descriptor: Sodium channel subunit beta-1, Sodium channel protein type 8 subunit alpha, Sodium channel subunit beta-2, ... (6 entities in total)
• Functional Keywords: ion channal, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 278284.96

Authors

Li, Y.,Jiang, D. (deposition date: 2022-09-24, release date: 2023-03-08, Last modification date: 2025-05-21)

Primary citation

Li, Y.,Yuan, T.,Huang, B.,Zhou, F.,Peng, C.,Li, X.,Qiu, Y.,Yang, B.,Zhao, Y.,Huang, Z.,Jiang, D.
Structure of human Na V 1.6 channel reveals Na + selectivity and pore blockade by 4,9-anhydro-tetrodotoxin.
Nat Commun, 14:1030-1030, 2023

PubMed Abstract: The sodium channel Na1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human Na1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of Na1.6 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 Na1.6 structure, ion conductance, and inhibition.

PubMed: 36823201
DOI: 10.1038/s41467-023-36766-9

Experimental method

ELECTRON MICROSCOPY (3.3 Å)