Interspecific and Intraspecific Variation in Venom Proteomics, Composition, and Antivenom Efficacy of Thai Cobras (Naja spp.): Highlighting the Distinct Profile of the Newly Identified Naja fuxi

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  Interspecific and Intraspecific Variation in Venom Proteomics, Composition, and Antivenom Efficacy of Thai Cobras (Naja spp.): Highlighting the Distinct Profile of the Newly Identified Naja fuxi Abstract Cobras ( Naja  spp.) account for a significant number of snakebite incidents in Thailand. The monocled cobra ( Naja kaouthia ) has historically been considered the only non-spitting species, but recent evidence indicates population-level diversification in central and southern regions. Additionally, a newly described non-spitting species, the mountain cobra ( Naja fuxi ), has been identified in mountainous areas. This study investigates venom variation among Thai  Naja  species and populations and evaluates the efficacy of monovalent and polyvalent Thai antivenoms. Proteomic analyses revealed that three-finger toxins dominate  Naja  venoms, whereas  N. fuxi  exhibits a distinct profile enriched in snake venom metalloproteinases and cysteine-rich...

Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I

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Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I

Abstract

Voltage-gated sodium channels (NaVs) 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 NaV isoforms, NaV1.8, 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-NaV1.8 and the Protoxin-I-bound complex at 3.1 Angstrom and 2.8 Angstrom resolution, respectively. The apo structure shows an unexpected movement of the Domain I S4-S5 helix, and VSDI was unresolvable. We find that Protoxin-I binds to and displaces the VSDII S3-S4 linker, hindering translocation of the S4II helix during activation.

Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I
Bryan Neumann, Stephen McCarthy, Shane Gonen, bioRxiv 2024.08.27.609828;