9YVL
Cryo-EM structure of the human TRPM4 channel in an open state bound to NC1 and PI(4,5)P2.
This is a non-PDB format compatible entry.
Summary for 9YVL
| Entry DOI | 10.2210/pdb9yvl/pdb |
| EMDB information | 73527 |
| Descriptor | Transient receptor potential cation channel subfamily M member 4, [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate, CALCIUM ION, ... (4 entities in total) |
| Functional Keywords | trpm4, ion channel, transport protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 550871.96 |
| Authors | Teixeira-Duarte, C.M.,Jiang, Y. (deposition date: 2025-10-23, release date: 2026-07-01, Last modification date: 2026-07-08) |
| Primary citation | Teixeira-Duarte, C.M.,Fu, W.,Zeng, W.,Wang, J.,Jiang, X.,Zhao, Z.,Zhong, Q.,Jiang, Y. Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload. Nat Commun, 2026 Cited by 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 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. PubMed: 42342693DOI: 10.1038/s41467-026-74814-2 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.78 Å) |
Structure validation
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