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- PDB-8rd9: human TRPM4 in SMA NBA -

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Basic information

Entry
Database: PDB / ID: 8rd9
Titlehuman TRPM4 in SMA NBA
ComponentsTransient receptor potential cation channel subfamily M member 4
KeywordsMEMBRANE PROTEIN / trpm / inhibitor
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
: / CHOLESTEROL / Transient receptor potential cation channel subfamily M member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsEkundayo, B. / Prakash, A. / Christian, G. / Anne, F.H. / Sabrina, G. / Mey, B. / Daniela, R. / Martin, L. / Jean, S.R. / Henning, S. ...Ekundayo, B. / Prakash, A. / Christian, G. / Anne, F.H. / Sabrina, G. / Mey, B. / Daniela, R. / Martin, L. / Jean, S.R. / Henning, S. / Hugues, A. / Dongchun, N.
Funding support Switzerland, 2items
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, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily M member 4
E: Transient receptor potential cation channel subfamily M member 4
C: Transient receptor potential cation channel subfamily M member 4
D: Transient receptor potential cation channel subfamily M member 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)340,63516
Polymers336,1194
Non-polymers4,51612
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 84029.695 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPM4 / Production host: Homo sapiens (human) / References: UniProt: Q8TD43
#2: Chemical
ChemComp-A1H0C / 4-chloranyl-2-(2-naphthalen-1-yloxyethanoylamino)benzoic acid


Mass: 355.772 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H14ClNO4
#3: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C27H46O
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: homotetramer / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 500 kDa/nm / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: OTHER / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
7Cootmodel fitting
9PHENIXmodel refinement
CTF correctionType: NONE
3D reconstructionResolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 50000 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
Atomic model buildingPDB-ID: 6BQV

6bqv


Accession code: 6BQV / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00320128
ELECTRON MICROSCOPYf_angle_d0.81627250
ELECTRON MICROSCOPYf_dihedral_angle_d5.0772666
ELECTRON MICROSCOPYf_chiral_restr0.0423030
ELECTRON MICROSCOPYf_plane_restr0.0063392

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