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- EMDB-72406: Cryo-EM structure of the human TRPM4 channel in complex with EGTA... -

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Basic information

Entry
Database: EMDB / ID: EMD-72406
TitleCryo-EM structure of the human TRPM4 channel in complex with EGTA and DAB at 37 degrees Celsius
Map data
Sample
  • Complex: Cryo-EM structure of the human TRPM4 channel in complex with EGTA and DAB at 37 degrees Celsius
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 4
  • Ligand: 4,4'-[(pyridin-2-yl)methylene]diphenol
Keywordsion channel / TRP channel / MEMBRANE 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 / cellular response to ATP / sodium channel activity / positive regulation of vasoconstriction / monoatomic cation transmembrane transport / regulation of heart rate by cardiac conduction / protein sumoylation / negative regulation of osteoblast differentiation / positive regulation of insulin secretion involved in cellular response to glucose stimulus / positive regulation of fat cell differentiation / 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: 3.2 Å
AuthorsJinhong H / Wei L / Juan D
Funding support United States, 9 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL153219 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS129804 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS111031 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS112363 United States
Other privateMcKnight Scholar Award
Other privateKlingenstein-Simon Scholar Award
Other privateSloan Research Fellowship
Other privatePew Scholar in the Biomedical Sciences
American Heart Association24POST1196982 United States
CitationJournal: Nat Commun / Year: 2026
Title: Noncanonical calcium-independent TRPM4 activation governs intestinal fluid homeostasis.
Authors: Yaru Liu / Jinhong Hu / Chu Xue / Wenjie Huang / Sofia Ievleva / Wei Lü / Juan Du / Zhengyu Cao /
Abstract: Imbalance in intestinal fluid homeostasis leads to nutrient malabsorption, intestinal tissue destruction, and systemic inflammation. Transient receptor potential melastatin 4 (TRPM4) is a calcium- ...Imbalance in intestinal fluid homeostasis leads to nutrient malabsorption, intestinal tissue destruction, and systemic inflammation. Transient receptor potential melastatin 4 (TRPM4) is a calcium-activated, non-selective monovalent cation channel converting chemical signals (Ca) into electrical signals (membrane depolarization). Here, we show the TRPM4 channel as a direct target of bisacodyl (BIC), a widely used clinical drug for chronic constipation management, and its active metabolite, deacetyl bisacodyl (DAB). DAB-induced laxative effects are abolished in global and intestinal epithelium-specific TRPM4-knockout mice, establishing the essential role of TRPM4 in intestinal fluid regulation. Furthermore, our structural work reveals DAB bound to an uncharacterized pocket, marking it as a non-Ca TRPM4 agonist and unveiling a noncanonical Ca-independent activation mechanism. Additionally, we delineate a signaling axis, TRPM4 → VGCC/NCX → ANO1, that governs ion homeostasis in the epithelium. Together, these findings establish TRPM4 as a key regulator of intestinal fluid balance and reveal its noncanonical calcium-independent activation as a therapeutic strategy for constipation.
History
DepositionAug 31, 2025-
Header (metadata) releaseFeb 4, 2026-
Map releaseFeb 4, 2026-
UpdateFeb 4, 2026-
Current statusFeb 4, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72406.png

Downloads & links

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Map

FileDownload / File: emd_72406.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 384 pix.
= 317.952 Å		0.83 Å/pix.
x 384 pix.
= 317.952 Å		0.83 Å/pix.
x 384 pix.
= 317.952 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.828 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.003
Minimum - Maximum-0.00490952 - 0.013498375
Average (Standard dev.)0.0000123799455 (±0.00054483913)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 317.952 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_72406_additional_1.map
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Half map: #1

Fileemd_72406_half_map_1.map
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Half map: #2

Fileemd_72406_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of the human TRPM4 channel in complex with EGTA...

EntireName: Cryo-EM structure of the human TRPM4 channel in complex with EGTA and DAB at 37 degrees Celsius
Components
  • Complex: Cryo-EM structure of the human TRPM4 channel in complex with EGTA and DAB at 37 degrees Celsius
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 4
  • Ligand: 4,4'-[(pyridin-2-yl)methylene]diphenol

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Supramolecule #1: Cryo-EM structure of the human TRPM4 channel in complex with EGTA...

SupramoleculeName: Cryo-EM structure of the human TRPM4 channel in complex with EGTA and DAB at 37 degrees Celsius
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: 4,4'-[(pyridin-2-yl)methylene]diphenol

MacromoleculeName: 4,4'-[(pyridin-2-yl)methylene]diphenol / type: ligand / ID: 2 / Number of copies: 4 / Formula: A1CR0
Molecular weightTheoretical: 277.317 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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.5 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 537300
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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