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| Title | Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload. |
|---|---|
| Journal, issue, pages | Biorxiv, Year 2026 |
| Publish date | Oct 23, 2025 (structure data deposition date) |
Authors | Celso M Teixeira-Duarte / Wan Fu / Weizhong Zeng / Jianghuang Wang / Xinzhe Jiang / Ziye Zhao / Qing Zhong / Youxing Jiang / ![]() |
| PubMed 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 ...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. |
External links | Biorxiv / PubMed:41659621 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.81 Å |
| Structure data | ![]() PDB-9yvp: |
| Chemicals | ![]() ChemComp-CA: ![]() ChemComp-PT5: ![]() PDB-1cy8: |
| Source |
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Keywords | TRANSPORT PROTEIN / TRPM4 / Ion channel |
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