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- EMDB-19073: human TRPM4 LMNG ligand CA -

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Basic information

Entry
Database: EMDB / ID: EMD-19073
Titlehuman TRPM4 LMNG ligand CA
Map data
Sample
  • Complex: homotetramer
Keywordstrpm / inhibitor / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 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 8, 2023-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateFeb 12, 2025-
Current statusFeb 12, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19073.png

Downloads & links

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Map

FileDownload / File: emd_19073.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.19 Å/pix.
x 280 pix.
= 331.996 Å		1.19 Å/pix.
x 280 pix.
= 331.996 Å		1.19 Å/pix.
x 280 pix.
= 331.996 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1857 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.18
Minimum - Maximum-1.40682 - 1.884709
Average (Standard dev.)0.00027340467 (±0.04394081)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 331.996 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_19073_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_19073_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : homotetramer

EntireName: homotetramer
Components
  • Complex: homotetramer

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Supramolecule #1: homotetramer

SupramoleculeName: homotetramer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 500 kDa/nm

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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
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN 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: 2.8 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

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