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- EMDB-19069: human TRPM4 in SMA NBA -

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Basic information

Entry
Database: EMDB / ID: EMD-19069
Titlehuman TRPM4 in SMA NBA
Map data
Sample
  • Complex: homotetramer
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 4
  • Ligand: 4-chloranyl-2-(2-naphthalen-1-yloxyethanoylamino)benzoic acid
  • Ligand: CHOLESTEROL
Keywordstrpm / inhibitor / 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 / metal ion transport / membrane depolarization during bundle of His cell action potential / membrane depolarization during Purkinje myocyte cell action potential / 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 / metal ion transport / membrane depolarization during bundle of His cell action potential / membrane depolarization during Purkinje myocyte cell action potential / negative regulation of bone mineralization / regulation of ventricular cardiac muscle cell action potential / calcium-activated cation channel activity / sodium ion import across plasma membrane / inorganic cation transmembrane transport / dendritic cell chemotaxis / TRP channels / cellular response to ATP / sodium channel activity / monoatomic cation transmembrane transport / regulation of heart rate by cardiac conduction / positive regulation of insulin secretion involved in cellular response to glucose stimulus / protein sumoylation / negative regulation of osteoblast differentiation / positive regulation of fat cell differentiation / positive regulation of heart rate / positive regulation of adipose tissue development / positive regulation of vasoconstriction / 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 / 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: 4.3 Å
AuthorsEkundayo B / Prakash A / Christian G / Anne FH / Sabrina G / Mey B / Daniela R / Martin L / Jean SR / Henning S ...Ekundayo B / Prakash A / Christian G / Anne FH / Sabrina G / Mey B / Daniela R / Martin L / Jean SR / Henning S / Hugues A / Dongchun N
Funding support Switzerland, 2 items
OrganizationGrant numberCountry
Swiss National Science FoundationCRSII5_177195 Switzerland
Swiss National Science FoundationNCCR TransCure (185544) Switzerland
CitationJournal: Nat Commun / Year: 2025
Title: Identification of a binding site for small molecule inhibitors targeting human TRPM4.
Authors: Babatunde Ekundayo / Prakash Arullampalam / Christian E Gerber / Anne-Flore Hämmerli / Sabrina Guichard / Mey Boukenna / Daniela Ross-Kaschitza / Martin Lochner / Jean-Sebastien Rougier / ...Authors: Babatunde Ekundayo / Prakash Arullampalam / Christian E Gerber / Anne-Flore Hämmerli / Sabrina Guichard / Mey Boukenna / Daniela Ross-Kaschitza / Martin Lochner / Jean-Sebastien Rougier / Henning Stahlberg / Hugues Abriel / Dongchun Ni /
Abstract: Transient receptor potential (TRP) melastatin 4 (TRPM4) protein is a calcium-activated monovalent cation channel associated with various genetic and cardiovascular disorders. The anthranilic acid ...Transient receptor potential (TRP) melastatin 4 (TRPM4) protein is a calcium-activated monovalent cation channel associated with various genetic and cardiovascular disorders. The anthranilic acid derivative NBA is a potent and specific TRPM4 inhibitor, but its binding site in TRPM4 has been unknown, although this information is crucial for drug development targeting TRPM4. We determine three cryo-EM structures of full-length human TRPM4 embedded in native lipid nanodiscs without inhibitor, bound to NBA, and an anthranilic acid derivative, IBA. We found that the small molecules NBA and IBA were bound in a pocket formed between the S3, S4, and TRP helices and the S4-S5 linker of TRPM4. Our structural data and results from patch clamp experiments enable validation of a binding site for small molecule inhibitors, paving the way for further drug development targeting TRPM4.
History
DepositionDec 7, 2023-
Header (metadata) releaseDec 18, 2024-
Map releaseDec 18, 2024-
UpdateFeb 5, 2025-
Current statusFeb 5, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19069.png

Downloads & links

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Map

FileDownload / File: emd_19069.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.45 Å/pix.
x 200 pix.
= 290.4 Å		1.45 Å/pix.
x 200 pix.
= 290.4 Å		1.45 Å/pix.
x 200 pix.
= 290.4 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.452 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.126
Minimum - Maximum-0.21131329 - 0.5619827
Average (Standard dev.)0.0067014727 (±0.027953975)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 290.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_19069_additional_1.map
Projections & Slices
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Half map: #2

Fileemd_19069_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_19069_half_map_2.map
Projections & Slices
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Sample components

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Entire : homotetramer

EntireName: homotetramer
Components
  • Complex: homotetramer
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 4
  • Ligand: 4-chloranyl-2-(2-naphthalen-1-yloxyethanoylamino)benzoic acid
  • Ligand: CHOLESTEROL

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Supramolecule #1: homotetramer

SupramoleculeName: homotetramer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 500 kDa/nm

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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: 84.029695 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: WRSFHLEASL MDALLNDRPE FVRLLISHGL SLGHFLTPMR LAQLYSAAPS NSLIRNLLDQ ASHSAGTKAP ALKGGAAELR PPDVGHVLR MLLGKMCAPR YPSGGAWDPH PGQGFGESMY LLSDKATSPL SLDAGLGQAP WSDLLLWALL LNRAQMAMYF W EMGSNAVS ...String:
WRSFHLEASL MDALLNDRPE FVRLLISHGL SLGHFLTPMR LAQLYSAAPS NSLIRNLLDQ ASHSAGTKAP ALKGGAAELR PPDVGHVLR MLLGKMCAPR YPSGGAWDPH PGQGFGESMY LLSDKATSPL SLDAGLGQAP WSDLLLWALL LNRAQMAMYF W EMGSNAVS SALGACLLLR VMARLEPDAE EAARRKDLAF KFEGMGVDLF GECYRSSEVR AARLLLRRCP LWGDATCLQL AM QADARAF FAQDGVQSLL TQKWWGDMAS TTPIWALVLA FFCPPLIYTR LITFRKSEEE PTREELEFDM DSVINGEGPV GTA DPAEKT PLGVPRQSGR PGCCGGRCGG RRCLRRWFHF WGAPVTIFMG NVVSYLLFLL LFSRVLLVDF QPAPPGSLEL LLYF WAFTL LCEELRQGLS GGGGSLASGG PGPGHASLSQ RLRLYLADSW NQCDLVALTC FLLGVGCRLT PGLYHLGRTV LCIDF MVFT VRLLHIFTVN KQLGPKIVIV SKMMKDVFFF LFFLGVWLVA YGVATEGLLR PRDSDFPSIL RRVFYRPYLQ IFGQIP QED MDVALMEHSN CSSEPGFWAH PPGAQAGTCV SQYANWLVVL LLVIFLLVAN ILLVNLLIAM FSYTFGKVQG NSDLYWK AQ RYRLIREFHS RPALAPPFIV ISHLRLLLRQ LCRRPRSPQP SSPALEHFRV YLSKEAERKL LTWESVHKEN FLLARARD K RESDSERLKR TSQKVDLALK QLGHIREY

UniProtKB: Transient receptor potential cation channel subfamily M member 4

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Macromolecule #2: 4-chloranyl-2-(2-naphthalen-1-yloxyethanoylamino)benzoic acid

MacromoleculeName: 4-chloranyl-2-(2-naphthalen-1-yloxyethanoylamino)benzoic acid
type: ligand / ID: 2 / Number of copies: 4 / Formula: A1H0C
Molecular weightTheoretical: 355.772 Da

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 8 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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

Concentration1 mg/mL
BufferpH: 8
GridModel: Quantifoil / Material: COPPER / Support film - Material: CARBON
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / 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: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: OTHER / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 50000
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6bqv


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-8rd9:
human TRPM4 in SMA NBA

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