9DBK

Full-length apo human voltage-gated sodium channel 1.8 (NaV1.8)

Summary for 9DBK

• Entry DOI: 10.2210/pdb9dbk/pdb
• EMDB information: 46718
• Descriptor: Sodium channel protein type 10 subunit alpha, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: ion channel, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 237945.59

Authors

Neumann, B.,McCarthy, S.,Gonen, S. (deposition date: 2024-08-23, release date: 2025-02-19)

Primary citation

Neumann, B.,McCarthy, S.,Gonen, S.
Structural basis of inhibition of human Na V 1.8 by the tarantula venom peptide Protoxin-I.
Nat Commun, 16:1459-1459, 2025

PubMed Abstract: Voltage-gated sodium channels (Nas) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine human Na isoforms, Na1.8, is a promising target for analgesics, and selective inhibitors are of interest as therapeutics. One such inhibitor, the gating-modifier peptide Protoxin-I derived from tarantula venom, blocks channel opening by shifting the activation voltage threshold to more depolarized potentials, but the structural basis for this inhibition has not previously been determined. Using monolayer graphene grids, we report the cryogenic electron microscopy structures of full-length human apo-Na1.8 and the Protoxin-I-bound complex at 3.1 Å and 2.8 Å resolution, respectively. The apo structure shows an unexpected movement of the Domain I S4-S5 helix, and VSD was unresolvable. We find that Protoxin-I binds to and displaces the VSD S3-S4 linker, hindering translocation of the S4 helix during activation.

PubMed: 39920100
DOI: 10.1038/s41467-024-55764-z

Experimental method

ELECTRON MICROSCOPY (3.12 Å)