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- PDB-9yvp: Cryo-EM structure of the L900V;R993P;S1060R mutant mouse TRPM4 ch... -

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Basic information

Entry
Database: PDB / ID: 9yvp
TitleCryo-EM structure of the L900V;R993P;S1060R mutant mouse TRPM4 channel in an open state bound to NC1 and PI(4,5)P2.
ComponentsTransient receptor potential cation channel subfamily M member 4
KeywordsTRANSPORT PROTEIN / TRPM4 / Ion channel
Function / homology
Function and homology information


positive regulation of atrial cardiac muscle cell action potential / positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization / sodium channel complex / regulation of T cell cytokine production / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / negative regulation of bone mineralization / membrane depolarization during Purkinje myocyte cell action potential / TRP channels / metal ion transport ...positive regulation of atrial cardiac muscle cell action potential / positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization / sodium channel complex / regulation of T cell cytokine production / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / negative regulation of bone mineralization / membrane depolarization during Purkinje myocyte cell action potential / TRP channels / metal ion transport / voltage-gated monoatomic ion channel activity / regulation of ventricular cardiac muscle cell action potential / calcium-activated cation channel activity / sodium ion import across plasma membrane / : / dendritic cell chemotaxis / cellular response to ATP / regulation of heart rate by cardiac conduction / monoatomic cation transmembrane transport / protein sumoylation / positive regulation of vasoconstriction / negative regulation of osteoblast differentiation / positive regulation of fat cell differentiation / long-term memory / positive regulation of heart rate / positive regulation of adipose tissue development / positive regulation of insulin secretion involved in cellular response to glucose stimulus / calcium-mediated signaling / regulation of membrane potential / calcium channel activity / calcium ion transport / positive regulation of canonical Wnt signaling pathway / positive regulation of cytosolic calcium ion concentration / protein homotetramerization / adaptive immune response / calmodulin binding / neuronal cell body / calcium ion binding / positive regulation of cell population proliferation / Golgi apparatus / endoplasmic reticulum / nucleoplasm / ATP binding / membrane / identical protein binding / plasma membrane
Similarity search - Function
TRPM, SLOG domain / : / : / SLOG in TRPM / TRPM2-like domain / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
: / Chem-PT5 / Transient receptor potential cation channel subfamily M member 4
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.81 Å
AuthorsTeixeira-Duarte, C.M. / Jiang, Y.
Funding support United States, 3items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM140892 United States
Welch FoundationI-1578 United States
Citation
Journal: bioRxiv / Year: 2026
Title: Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload.
Authors: Celso M Teixeira-Duarte / Wan Fu / Weizhong Zeng / Jianghuang Wang / Xinzhe Jiang / Ziye Zhao / Qing Zhong / Youxing Jiang /
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.
#1: Journal: Nat Commun / Year: 2026
Title: Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload
Authors: Teixeira-Duarte, C.M. / Fu, W. / Zeng, W. / Wang, J. / Jiang, X. / Zhao, Z. / Zhong, Q. / Jiang, Y.
History
DepositionOct 23, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Transient receptor potential cation channel subfamily M member 4
A: Transient receptor potential cation channel subfamily M member 4
C: Transient receptor potential cation channel subfamily M member 4
D: Transient receptor potential cation channel subfamily M member 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)556,42816
Polymers550,6184
Non-polymers5,81112
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Transient receptor potential cation channel subfamily M member 4 / Calcium-activated non-selective cation channel 1 / Long transient receptor potential channel 4 / ...Calcium-activated non-selective cation channel 1 / Long transient receptor potential channel 4 / LTrpC-4 / LTrpC4


Mass: 137654.406 Da / Num. of mol.: 4 / Mutation: L900V, R993P, S1060R
Source method: isolated from a genetically manipulated source
Details: C terminal thrombin cleavage site and FLAG tag / Source: (gene. exp.) Mus musculus (house mouse) / Gene: Trpm4, Ltrpc4 / Production host: Homo sapiens (human) / References: UniProt: Q7TN37
#2: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-PT5 / [(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 / Phosphatidylinositol 4,5-bisphosphate / PtdIns(4,5)P2


Mass: 1047.088 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C47H85O19P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#4: Chemical
ChemComp-A1CY8 / Necrocide 1 / (3S)-3-cycloheptyl-3-(4-hydroxyphenyl)-6-methoxy-7-methyl-1,3-dihydro-2H-indol-2-one


Mass: 365.465 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H27NO3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: mouse TRPM4 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
7Coot1.1.18model fitting
9PHENIX1.21.2_5419model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 2.81 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 19675 / Symmetry type: POINT
RefinementHighest resolution: 2.81 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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