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- EMDB-48563: Cryo-EM structure of the human TRPM4 channel in a calcium and PI(... -

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Basic information

Entry
Database: EMDB / ID: EMD-48563
TitleCryo-EM structure of the human TRPM4 channel in a calcium and PI(4,5)P2 bound open state
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: CALCIUM ION
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 / 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 / negative regulation of bone mineralization / 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 / 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 / negative regulation of bone mineralization / 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 / positive regulation of vasoconstriction / cellular response to ATP / monoatomic cation transmembrane transport / regulation of heart rate by cardiac conduction / protein sumoylation / negative regulation of osteoblast differentiation / positive regulation of fat cell differentiation / positive regulation of insulin secretion involved in cellular response to glucose stimulus / positive regulation of heart rate / positive regulation of adipose tissue development / calcium-mediated signaling / calcium ion transmembrane transport / calcium channel activity / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of canonical Wnt signaling pathway / 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 / endoplasmic reticulum / Golgi apparatus / nucleoplasm / ATP binding / identical protein binding / membrane / 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: 2.44 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 Struct Mol Biol / Year: 2025
Title: Structural landscape of activation, desensitization and inhibition in the human TRPM4 channel.
Authors: Celso M Teixeira-Duarte / Weizhong Zeng / Youxing Jiang /
Abstract: TRPM4 is a member of the transient receptor potential melastatin channel subfamily and functions as a Ca-activated monovalent-selective cation channel. It is widely expressed in various cells and ...TRPM4 is a member of the transient receptor potential melastatin channel subfamily and functions as a Ca-activated monovalent-selective cation channel. It is widely expressed in various cells and tissues, where its activation depolarizes the plasma membrane potential and modulates various Ca-dependent biological processes. TRPM4 activity is potentiated by membrane phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P) and inhibited by cytosolic free adenosine triphosphate (ATP), allowing the channel to transition between different functional states in response to dynamic changes in cellular Ca, ATP and PtdIns(4,5)P levels during signaling events. Here we present single-particle cryo-electron microscopy structures of human TRPM4 in four distinct states: apo closed, Ca-bound putative desensitized, Ca-PtdIns(4,5)P-bound open and ATP-bound inhibited. Combined with mutagenesis and electrophysiological analyses, these structures reveal the molecular mechanisms underlying TRPM4 activation, desensitization and inhibition. Given the central roles of Ca, PtdIns(4,5)P and ATP in cellular signaling, this work provides a structural foundation to decipher the physiological functions of TRPM4 across diverse biological systems.
History
DepositionJan 8, 2025-
Header (metadata) releaseOct 29, 2025-
Map releaseOct 29, 2025-
UpdateNov 12, 2025-
Current statusNov 12, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48563.png

Downloads & links

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Map

FileDownload / File: emd_48563.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.)
0.74 Å/pix.
x 360 pix.
= 265.68 Å		0.74 Å/pix.
x 360 pix.
= 265.68 Å		0.74 Å/pix.
x 360 pix.
= 265.68 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.738 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.17
Minimum - Maximum-0.6409286 - 0.92884517
Average (Standard dev.)0.0053994986 (±0.036570475)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 265.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: hTRPM4 Ca PIP2 open Half map A

Fileemd_48563_half_map_1.map
AnnotationhTRPM4_Ca_PIP2_open_Half_map_A
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: hTRPM4 Ca PIP2 open Half map B

Fileemd_48563_half_map_2.map
AnnotationhTRPM4_Ca_PIP2_open_Half_map_B
Projections & Slices
AxesZYX

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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: CALCIUM ION

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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 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 134.456484 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVVPEKEQSW IPKIFKKKTC TTFIVDSTDP GGTLCQCGRP RTAHPAVAME DAFGAAVVTV WDSDAHTTEK PTDAYGELDF TGAGRKHSN FLRLSDRTDP AAVYSLVTRT WGFRAPNLVV SVLGGSGGPV LQTWLQDLLR RGLVRAAQST GAWIVTGGLH T GIGRHVGV ...String:
MVVPEKEQSW IPKIFKKKTC TTFIVDSTDP GGTLCQCGRP RTAHPAVAME DAFGAAVVTV WDSDAHTTEK PTDAYGELDF TGAGRKHSN FLRLSDRTDP AAVYSLVTRT WGFRAPNLVV SVLGGSGGPV LQTWLQDLLR RGLVRAAQST GAWIVTGGLH T GIGRHVGV AVRDHQMAST GGTKVVAMGV APWGVVRNRD TLINPKGSFP ARYRWRGDPE DGVQFPLDYN YSAFFLVDDG TH GCLGGEN RFRLRLESYI SQQKTGVGGT GIDIPVLLLL IDGDEKMLTR IENATQAQLP CLLVAGSGGA ADCLAETLED TLA PGSGGA RQGEARDRIR RFFPKGDLEV LQAQVERIMT RKELLTVYSS EDGSEEFETI VLKALVKACG SSEASAYLDE LRLA VAWNR VDIAQSELFR GDIQWRSFHL EASLMDALLN DRPEFVRLLI SHGLSLGHFL TPMRLAQLYS AAPSNSLIRN LLDQA SHSA GTKAPALKGG AAELRPPDVG HVLRMLLGKM CAPRYPSGGA WDPHPGQGFG ESMYLLSDKA TSPLSLDAGL GQAPWS DLL LWALLLNRAQ MAMYFWEMGS NAVSSALGAC LLLRVMARLE PDAEEAARRK DLAFKFEGMG VDLFGECYRS SEVRAAR LL LRRCPLWGDA TCLQLAMQAD ARAFFAQDGV QSLLTQKWWG DMASTTPIWA LVLAFFCPPL IYTRLITFRK SEEEPTRE E LEFDMDSVIN GEGPVGTADP AEKTPLGVPR QSGRPGCCGG RCGGRRCLRR WFHFWGAPVT IFMGNVVSYL LFLLLFSRV LLVDFQPAPP GSLELLLYFW AFTLLCEELR QGLSGGGGSL ASGGPGPGHA SLSQRLRLYL ADSWNQCDLV ALTCFLLGVG CRLTPGLYH LGRTVLCIDF MVFTVRLLHI FTVNKQLGPK IVIVSKMMKD VFFFLFFLGV WLVAYGVATE GLLRPRDSDF P SILRRVFY RPYLQIFGQI PQEDMDVALM EHSNCSSEPG FWAHPPGAQA GTCVSQYANW LVVLLLVIFL LVANILLVNL LI AMFSYTF GKVQGNSDLY WKAQRYRLIR EFHSRPALAP PFIVISHLRL LLRQLCRRPR SPQPSSPALE HFRVYLSKEA ERK LLTWES VHKENFLLAR ARDKRESDSE RLKRTSQKVD LALKQLGHIR EYEQRLKVLE REVQQCSRVL GWVAEALSRS ALLP PGGPP PPDLPGSKD

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: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 8 / Formula: CA
Molecular weightTheoretical: 40.078 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 / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k 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:

6bqv

Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.44 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 32765
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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