Structural Basis of Inhibition of Human Na1.8 by the Tarantula Venom Peptide Protoxin-I

Overview

Journal bioRxiv

Date 2024 Sep 10

PMID 39253517

Authors

Bryan Neumann

Stephen McCarthy

Shane Gonen

Affiliations

Soon will be listed here.

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 depolarised 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.

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