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Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload.

Overview

Authors: Celso M Teixeira-Duarte1,2, Wan Fu3, Weizhong Zeng1,2, Jianghuang Wang3, Xinzhe Jiang3, Ziye Zhao3, Qing Zhong3, Youxing Jiang1,2
ORCID iDs: Celso M Teixeira-Duarte, Wan Fu, Xinzhe Jiang, Qing Zhong, Youxing Jiang
  1. Howard Hughes Medical Institute and Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX USA
  2. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX USA
  3. Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People’s Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Institutions: Howard Hughes Medical Institute (United States); The University of Texas Southwestern Medical Center (United States); Shanghai Jiao Tong University (China); Shanghai Ninth People's Hospital (China)
Journal: Nature communications, volume 17, issue 1, article 7939
Dates: received 2 December 2025; accepted 15 June 2026; published online 24 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41467-026-74814-2 · PMID 42342693 · PMCID PMC13448252 · OpenAlex W7165813026
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: histology / microscopy (modality), human (organism), mouse (organism), cellular / molecular (subfield)
Methods: Evoked potentials, fMRI & imaging
Keywords: Cryoelectron microscopy, Ion channels, Cell death
MeSH: Necrosis*, Sodium*, TRPM Cation Channels*, Animals, Binding Sites, Cryoelectron Microscopy, HEK293 Cells, Humans, Mice (* major topic)
Topic: Ion Channels and Receptors (Sensory Systems, Neuroscience), according to OpenAlex
Funding: National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund) (32530055, W2511018, 82504119); Howard Hughes Medical Institute
Citations: not cited yet (Europe PMC); 67 references in the paper

Abstract

The small molecule Necrocide 1 (NC1) constitutively activates human TRPM4, triggering Na⁺ influx and leading to necrotic cell death, a process termed Necrosis by Sodium Overload (NECSO). NC1 activation is specific to human TRPM4 and does not affect most of the other mammalian TRPM4 orthologs. Here, we elucidate the molecular mechanism underlying NC1 activation and its species-specific selectivity for human TRPM4 using a combination of single-particle cryo-EM, electrophysiology, and cell death assays. We identify the NC1-binding site and the key molecular determinants responsible for channel activation. In addition, we explain the insensitivity of mouse TRPM4 to NC1 and pinpoint specific residues that define NC1 specificity for human TRPM4. Given the upregulation of TRPM4 in various human cancers, our mechanistic insights into NC1 activation and specificity provide a framework for the potential development of cancer therapeutics targeting TRPM4-mediated necrosis.

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

Code

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Data

Datasets cited

Data availability

The cryo-EM density maps of the human TRPM4 have been deposited in the Electron Microscopy Data Bank (EMDB) under accession numbers EMD-73526 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-73526) (NC1-bound in the presence of EGTA), EMD-73527 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-73527) (NC1/PI(4,5)P2-bound), and EMD-73528 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-73528) (NC1/PI(4,5)P2-bound in the presence of EGTA). Atomic coordinates have been deposited in the Protein Data Bank (PDB) under accession numbers 9YVK (http://doi.org/10.2210/pdb9YVK/pdb) (NC1-bound in the presence of EGTA), 9YVL (http://doi.org/10.2210/pdb9YVL/pdb) (NC1/PI(4,5)P2-bound), and 9YVM (http://doi.org/10.2210/pdb9YVM/pdb) (NC1/PI(4,5)P2-bound in the presence of EGTA). The cryo-EM density maps of the mouse TRPM4 have been deposited in the Electron Microscopy Data Bank (EMDB) under accession numbers EMD-73530 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-73530) (NC1/PI(4,5)P2-bound wild-type mTRPM4), EMD-73529 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-73529) (NC1-bound wild-type mTRPM4), and EMD-73531 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-73531) (NC1/PI(4,5)P2-bound L900V/R993P/S1060R triple mutant mTRPM4). Atomic coordinates have been deposited in the Protein Data Bank (PDB) under accession numbers 9YVO (http://doi.org/10.2210/pdb9YVO/pdb) (NC1/PI(4,5)P2-bound wild-type mTRPM4), 9YVN (http://doi.org/10.2210/pdb9YVN/pdb) (NC1-bound wild-type mTRPM4), and 9YVP (http://doi.org/10.2210/pdb9YVP/pdb) (NC1/PI(4,5)P2-bound L900V/R993P/S1060R triple mutant mTRPM4). Atomic coordinates previously published and used for comparisons in this study are deposited in the Protein Data Bank (PDB) under accession numbers: 9MRT (http://doi.org/10.2210/pdb9MRT/pdb) (hTRPM4 Ca2+/PI(4,5)P2-Open), 9MT8 (http://doi.org/10.2210/pdb9MT8/pdb) (hTRPM4 Ca2+-Putative desensitized), 9MTA (http://doi.org/10.2210/pdb9MTA/pdb) (hTRPM4 Apo-Closed), and 6BCJ (http://doi.org/10.2210/pdb6BCJ/pdb) (mTRPM4 Apo-Closed). Cryo-EM density maps previously published and used for comparisons in this study are deposited in the Electron Microscopy Data Bank (EMDB) under accession numbers EMD-48563 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-48563) (hTRPM4 Ca2+/PI(4,5)P2-Open), EMD-48603 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-48603) (hTRPM4 Ca2+-Putative desensitized), EMD-48604 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-48604) (hTRPM4 Apo-Closed) and EMD-7081 (https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-7081) (mTRPM4 Apo-Closed). All the data pertaining to the electrophysiology and cell viability assays is provided in the Source Data files. All other data and materials supporting the findings of this study can be obtained from the corresponding authors upon request. 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, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 8 authors, 3 keywords, 9 MeSH terms, 2 funders, 66 references.

Cite

This paper

Teixeira-Duarte, C. M., Fu, W., Zeng, W., Wang, J., Jiang, X., Zhao, Z., Zhong, Q., & Jiang, Y. (2026). Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload. Nature communications, 17(1), 7939. https://doi.org/10.1038/s41467-026-74814-2

BibTeX

@article{teixeiraduarte2026structural,
author = {Teixeira-Duarte, Celso M and Fu, Wan and Zeng, Weizhong and Wang, Jianghuang and Jiang, Xinzhe and Zhao, Ziye and Zhong, Qing and Jiang, Youxing},
title = {{Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload}},
journal = {Nature communications},
year = {2026},
month = jun,
volume = {17},
number = {1},
pages = {7939},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/s41467-026-74814-2},
url = {https://doi.org/10.1038/s41467-026-74814-2},
pmid = {42342693},
pmcid = {PMC13448252}
}

RIS

TY - JOUR
AU - Teixeira-Duarte, Celso M
AU - Fu, Wan
AU - Zeng, Weizhong
AU - Wang, Jianghuang
AU - Jiang, Xinzhe
AU - Zhao, Ziye
AU - Zhong, Qing
AU - Jiang, Youxing
TI - Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/06/24
VL - 17
IS - 1
SP - 7939
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/s41467-026-74814-2
UR - https://doi.org/10.1038/s41467-026-74814-2
LA - en
ER -

CSL-JSON

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