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- EMDB-73528: Cryo-EM structure of the human TRPM4 channel in an open state bou... -

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Basic information

Entry
Database: EMDB / ID: EMD-73528
TitleCryo-EM structure of the human TRPM4 channel in an open state bound to NC1 and PI(4,5)P2 in the presence of EGTA.
Map data
Sample
  • Complex: human TRPM4
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 4
  • Ligand: [(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
  • Ligand: Necrocide 1
KeywordsTRPM4 / Ion channel / TRANSPORT PROTEIN
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 / negative regulation of bone mineralization / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / membrane depolarization during Purkinje myocyte cell action potential / metal ion transport / regulation of ventricular cardiac muscle cell action potential ...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 / negative regulation of bone mineralization / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / membrane depolarization during Purkinje myocyte cell action potential / metal ion transport / regulation of ventricular cardiac muscle cell action potential / calcium-activated cation channel activity / sodium ion import across plasma membrane / dendritic cell chemotaxis / TRP channels / sodium channel activity / cellular response to ATP / regulation of heart rate by cardiac conduction / monoatomic cation transmembrane transport / positive regulation of fat cell differentiation / protein sumoylation / positive regulation of vasoconstriction / negative regulation of osteoblast differentiation / 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 / calcium ion transmembrane transport / calcium channel activity / transmembrane transport / positive regulation of canonical Wnt signaling pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of cytosolic calcium ion concentration / protein homotetramerization / adaptive immune response / calmodulin binding / neuronal cell body / positive regulation of cell population proliferation / calcium ion binding / Golgi apparatus / endoplasmic reticulum / 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
Transient receptor potential cation channel subfamily M member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.73 Å
AuthorsTeixeira-Duarte CM / Jiang Y
Funding support United States, 3 items
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
CitationJournal: Nat Commun / 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.
History
DepositionOct 23, 2025-
Header (metadata) releaseJul 1, 2026-
Map releaseJul 1, 2026-
UpdateJul 8, 2026-
Current statusJul 8, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_73528.png

Downloads & links

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Map

FileDownload / File: emd_73528.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 360 pix.
= 308.52 Å		0.86 Å/pix.
x 360 pix.
= 308.52 Å		0.86 Å/pix.
x 360 pix.
= 308.52 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.857 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy EMDB: 0.266
Minimum - Maximum-1.5352536 - 2.055318
Average (Standard dev.)0.0055353697 (±0.058026288)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 308.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_73528_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_73528_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : human TRPM4

EntireName: human TRPM4
Components
  • Complex: human TRPM4
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 4
  • Ligand: [(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
  • Ligand: Necrocide 1

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Supramolecule #1: human TRPM4

SupramoleculeName: human TRPM4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transient receptor potential cation channel subfamily M member 4

MacromoleculeName: Transient receptor potential cation channel subfamily M member 4
type: protein_or_peptide / ID: 1 / Details: N terminal FLAG tag and thrombin cleavage site / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 136.265359 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKG SGLVPRGSVV PEKEQSWIPK IFKKKTCTTF IVDSTDPGGT LCQCGRPRTA HPAVAMEDAF GAAVVTVWDS DAHTTEKPT DAYGELDFTG AGRKHSNFLR LSDRTDPAAV YSLVTRTWGF RAPNLVVSVL GGSGGPVLQT WLQDLLRRGL V RAAQSTGA ...String:
MDYKDDDDKG SGLVPRGSVV PEKEQSWIPK IFKKKTCTTF IVDSTDPGGT LCQCGRPRTA HPAVAMEDAF GAAVVTVWDS DAHTTEKPT DAYGELDFTG AGRKHSNFLR LSDRTDPAAV YSLVTRTWGF RAPNLVVSVL GGSGGPVLQT WLQDLLRRGL V RAAQSTGA WIVTGGLHTG IGRHVGVAVR DHQMASTGGT KVVAMGVAPW GVVRNRDTLI NPKGSFPARY RWRGDPEDGV QF PLDYNYS AFFLVDDGTH GCLGGENRFR LRLESYISQQ KTGVGGTGID IPVLLLLIDG DEKMLTRIEN ATQAQLPCLL VAG SGGAAD CLAETLEDTL APGSGGARQG EARDRIRRFF PKGDLEVLQA QVERIMTRKE LLTVYSSEDG SEEFETIVLK ALVK ACGSS EASAYLDELR LAVAWNRVDI AQSELFRGDI QWRSFHLEAS LMDALLNDRP EFVRLLISHG LSLGHFLTPM RLAQL YSAA PSNSLIRNLL DQASHSAGTK APALKGGAAE LRPPDVGHVL RMLLGKMCAP RYPSGGAWDP HPGQGFGESM YLLSDK ATS PLSLDAGLGQ APWSDLLLWA LLLNRAQMAM YFWEMGSNAV SSALGACLLL RVMARLEPDA EEAARRKDLA FKFEGMG VD LFGECYRSSE VRAARLLLRR CPLWGDATCL QLAMQADARA FFAQDGVQSL LTQKWWGDMA STTPIWALVL AFFCPPLI Y TRLITFRKSE EEPTREELEF DMDSVINGEG PVGTADPAEK TPLGVPRQSG RPGCCGGRCG GRRCLRRWFH FWGAPVTIF MGNVVSYLLF LLLFSRVLLV DFQPAPPGSL ELLLYFWAFT LLCEELRQGL SGGGGSLASG GPGPGHASLS QRLRLYLADS WNQCDLVAL TCFLLGVGCR LTPGLYHLGR TVLCIDFMVF TVRLLHIFTV NKQLGPKIVI VSKMMKDVFF FLFFLGVWLV A YGVATEGL LRPRDSDFPS ILRRVFYRPY LQIFGQIPQE DMDVALMEHS NCSSEPGFWA HPPGAQAGTC VSQYANWLVV LL LVIFLLV ANILLVNLLI AMFSYTFGKV QGNSDLYWKA QRYRLIREFH SRPALAPPFI VISHLRLLLR QLCRRPRSPQ PSS PALEHF RVYLSKEAER KLLTWESVHK ENFLLARARD KRESDSERLK RTSQKVDLAL KQLGHIREYE QRLKVLEREV QQCS RVLGW VAEALSRSAL LPPGGPPPPD LPGSKD

UniProtKB: Transient receptor potential cation channel subfamily M member 4

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Macromolecule #2: [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tr...

MacromoleculeName: [(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
type: ligand / ID: 2 / Number of copies: 4 / Formula: PT5
Molecular weightTheoretical: 1.047088 KDa

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Macromolecule #3: Necrocide 1

MacromoleculeName: Necrocide 1 / type: ligand / ID: 3 / Number of copies: 4 / Formula: A1CY8
Molecular weightTheoretical: 365.465 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.9 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

9mrt

Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.73 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 79688
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

SoftwareName: Coot (ver. 1.1.18)
Output model

PDB-9yvm:
Cryo-EM structure of the human TRPM4 channel in an open state bound to NC1 and PI(4,5)P2 in the presence of EGTA.

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