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Structural insights into insect-selective sodium channel toxins drive AI-enhanced biopesticide design.

Overview

Authors: Heng Jiang1, Ruibo Gao2,3,4, Huiqin Xu5, Cheng Wang6, Shuyue Ma1, Yishu Gong1, Lianyun Lin1, Lina Yang1, Xiang Li1, Ye Liu1, Rongcai Lu2,3,4, Jun-An Ma7, Jinbo Xu6, Ke Dong8, Filip Van Petegem9, Zheng Liu5, Shaoying Wu2,3,4, Zhiguang Yuchi1,10,11
ORCID iDs: Heng Jiang, Yishu Gong, Jun-An Ma, Jinbo Xu, Ke Dong, Filip Van Petegem, Zheng Liu, Shaoying Wu, Zhiguang Yuchi
  1. State Key Laboratory of Synthetic Biology; Frontiers Science Center for Synthetic Biology; Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency; School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University,Tianjin, China
  2. School of Breeding and Multiplication (Sanya Institute of Breeding and Multiplication), Hainan University,Sanya, Hainan China
  3. School of Life and Health Sciences, Hainan University,Haikou, Hainan China
  4. School of Tropical Agriculture and Forestry (School of Agricultural and Rural Affairs, School of Rural Revitalization), Hainan University,Danzhou, Hainan China
  5. Cryo-electron Microscopy Center and Department of Pharmacology, School of Medicine, Southern University of Science and Technology,Shenzhen Guangdong, China
  6. MoleculeMind Inc., Beijing, China
  7. Department of Chemistry, State Key Laboratory Synthetic Biology, Tianjin University,Tianjin, China
  8. Department of Biology, Duke University,Durham, NC USA
  9. Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia,Vancouver, BC Canada
  10. Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, China
  11. Guangdong Laboratory for Lingnan Modern Agriculture (Shenzhen Branch), Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences,Shenzhen Guangdong, China
Institutions: Tianjin University (China); Hainan University (China); Southern University of Science and Technology (China); Duke University (United States); University of British Columbia (Canada); Chinese Academy of Agricultural Sciences (China)
Journal: Nature communications, volume 17, issue 1, article 3543
Dates: received 2 April 2025; accepted 18 February 2026; published online 6 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41467-026-70190-z · PMID 41786748 · PMCID PMC13087302 · OpenAlex W7133995427
Open access: gold, a free copy (OpenAlex)
Status: code verified
Categories: histology / microscopy (modality), other (organism), cellular / molecular (subfield)
Keywords: Cryoelectron microscopy, Peptides, Sodium channels, Computational biophysics
MeSH: Insect Proteins*, Scorpion Venoms*, Voltage-Gated Sodium Channels*, Animals, Cryoelectron Microscopy, Models, Molecular, Pest Control, Biological, Scorpions, Sea Anemones, Sodium Channels (* major topic)
Topic: Ion channel regulation and function (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: National Natural Science Foundation of China (National Science Foundation of China) (32372580, 92156025, 32260666); Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China, JYB2025XDXM503 National Key Research and Development Program of China, 2025YFC3409400 Emerging Frontiers Cultivation Program of Tianjin University Interdisciplinary Center
Citations: not cited yet (Europe PMC); 69 references in the paper

Abstract

Many voltage-gated sodium channel-targeting animal peptide toxins are renowned for their potency and selectivity against insects. Understanding why these toxins selectively target insect sodium channels over their mammalian counterparts is crucial for developing safer and more effective pest control agents. Here, we present the cryoelectron microscopy (cryo-EM) structures of the insect sodium channel NavPaS bound to two naturally occurring insect-selective toxins, Av3 from the sea anemone and LqhαIT from the scorpion. Both toxins bind to the voltage-sensing domain 4 (VSD4) of NavPaS and disrupt fast inactivation by stabilizing the S4 segment in a deactivated conformation. While Av3 engages a membrane-embedded site between VSD4 and pore domain 1 (PD1), LqhαIT binds to the classical neurotoxin site 3, illustrating distinct binding modes that converge on a shared mechanism of action. These structures reveal the molecular determinants of insect selectivity and highlight the molecular coevolution of toxin-channel interactions, as corroborated by electrophysiology and toxicity assays. Leveraging these insights, we apply AI-driven protein design tools to increase the insecticidal potency of LqhαIT, resulting in a variant with a remarkable doubling in efficacy, as we confirm by insecticidal bioassays. This study illuminates the diverse mechanisms of sodium channel modulation and provides a framework for the structure-guided, AI-driven design of toxin-based biopesticides.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

No file of the authors' code could be read here: it is described below, and read at its source.

Zenodo 18150075

License: CC-BY-4.0
State: the link answers, verified on 30 September 2026
Evidence: files inventoried
Size: 1 file
Software Heritage: not checked
Found in: “Code availability”
Not found: README, license file, CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 1 check, the latest on 30 September 2026: the link answers (HTTP 200)
  • 30 September 2026: the link answers (HTTP 200)
At the source:

Code availability

The ComplexDDG code has been deposited in the Zenodo database (10.5281/zenodo.18150075)69. All other computational tools, including ESM-2 and A3D 2.0, are publicly available as described in references48,49.

Reproduced under the paper's license (CC BY), from the paper cited above.

Tracing map

Proposed by the machine: these links were found in the paper and verified at the source, without human review. The map will receive a Zenodo DOI once one of the paper's authors has validated it with their ORCID.

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  • 1 repository of the authors' code, each at its verified commit, with its license and how the link was found in the paper;
  • 0 scripts, each with its path and the digest of its content;
  • no match between paragraphs and code yet;
  • neither the text of the paper nor the code itself.

Its JSON (tracing-map.json) is deposited on Zenodo with its DOI once the map is validated.

Data

Datasets cited

Data availability

The cryo-EM maps have been deposited in the Electron Microscopy Data Bank (EMDB) under accession codes EMD-63108 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-63108) (NavPaS-Av3); and EMD-63189 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-63189) (NavPaS-LqhαIT). The atomic coordinates have been deposited in the Protein Data Bank (PDB) under accession codes 9LHZ (https://doi.org/10.2210/pdb9LHZ/pdb) (NavPaS-Av3); and 9LKZ (https://doi.org/10.2210/pdb9LKZ/pdb) (NavPaS-LqhαIT). The structures used in this paper are available in the PDB database under accession codes 1ANS (https://doi.org/10.2210/pdb1ANS/pdb), 2ASC (https://doi.org/10.2210/pdb2ASC/pdb), 5X0M (https://doi.org/10.2210/pdb5X0M/pdb), 6NT4 (https://doi.org/10.2210/pdb6NT4/pdb), 7DTD (https://doi.org/10.2210/pdb7DTD/pdb), 6J8E (https://doi.org/10.2210/pdb6J8E/pdb), 7W77 (https://doi.org/10.2210/pdb7W77/pdb), 6AGF (https://doi.org/10.2210/pdb6AGF/pdb), 7DTC (https://doi.org/10.2210/pdb7DTC/pdb), 8FHD (https://doi.org/10.2210/pdb8FHD/pdb), 7WE4 (https://doi.org/10.2210/pdb7WE4/pdb), 7TJ9 (https://doi.org/10.2210/pdb7TJ9/pdb), and 5XSY (https://doi.org/10.2210/pdb5XSY/pdb). Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 18 authors, 4 keywords, 10 MeSH terms, 2 funders, 68 references.

Cite

This paper

Jiang, H., Gao, R., Xu, H., Wang, C., Ma, S., Gong, Y., Lin, L., Yang, L., Li, X., Liu, Y., Lu, R., Ma, J.-A., Xu, J., Dong, K., Van Petegem, F., Liu, Z., Wu, S., & Yuchi, Z. (2026). Structural insights into insect-selective sodium channel toxins drive AI-enhanced biopesticide design. Nature communications, 17(1), 3543. https://doi.org/10.1038/s41467-026-70190-z

BibTeX

@article{jiang2026structural,
author = {Jiang, Heng and Gao, Ruibo and Xu, Huiqin and Wang, Cheng and Ma, Shuyue and Gong, Yishu and Lin, Lianyun and Yang, Lina and Li, Xiang and Liu, Ye and Lu, Rongcai and Ma, Jun-An and Xu, Jinbo and Dong, Ke and Van Petegem, Filip and Liu, Zheng and Wu, Shaoying and Yuchi, Zhiguang},
title = {{Structural insights into insect-selective sodium channel toxins drive AI-enhanced biopesticide design}},
journal = {Nature communications},
year = {2026},
month = mar,
volume = {17},
number = {1},
pages = {3543},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/s41467-026-70190-z},
url = {https://doi.org/10.1038/s41467-026-70190-z},
pmid = {41786748},
pmcid = {PMC13087302}
}

RIS

TY - JOUR
AU - Jiang, Heng
AU - Gao, Ruibo
AU - Xu, Huiqin
AU - Wang, Cheng
AU - Ma, Shuyue
AU - Gong, Yishu
AU - Lin, Lianyun
AU - Yang, Lina
AU - Li, Xiang
AU - Liu, Ye
AU - Lu, Rongcai
AU - Ma, Jun-An
AU - Xu, Jinbo
AU - Dong, Ke
AU - Van Petegem, Filip
AU - Liu, Zheng
AU - Wu, Shaoying
AU - Yuchi, Zhiguang
TI - Structural insights into insect-selective sodium channel toxins drive AI-enhanced biopesticide design
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/03/06
VL - 17
IS - 1
SP - 3543
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/s41467-026-70190-z
UR - https://doi.org/10.1038/s41467-026-70190-z
LA - en
ER -

CSL-JSON

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