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- PDB-9t9u: Cryo-EM composite structure of mouse TRPM3 alpha 2 in complex wit... -

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Basic information

Entry
Database: PDB / ID: 9t9u
TitleCryo-EM composite structure of mouse TRPM3 alpha 2 in complex with antagonist Ononetin
ComponentsMKIAA1616 protein
KeywordsMEMBRANE PROTEIN / Ca2+ channel Ononetin-bound Closed conformation
Function / homology
Function and homology information


protein tetramerization / calcium channel activity / calmodulin binding / plasma membrane
Similarity search - Function
TRPM, tetramerisation domain / TRPM, tetramerisation domain superfamily / Tetramerisation domain of TRPM / TRPM, SLOG domain / : / : / SLOG in TRPM / TRPM2-like domain / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / : / (25R)-14beta,17beta-spirost-5-en-3beta-ol / Transient receptor potential cation channel subfamily M member 3
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsShkumatov, A.V. / Schenck, S. / Brunner, J.D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2026
Title: Stereoselectivity and functional plasticity of a common ligand-binding pocket in TRPM3.
Authors: Bahar Bazeli / Alexander V Shkumatov / Stephan Schenck / Jean-Christophe Vanherck / Annelies Janssens / Stéphane A H Spieser / Damien Marchand / Robbe Roelens / Patrick Chaltin / Arnaud ...Authors: Bahar Bazeli / Alexander V Shkumatov / Stephan Schenck / Jean-Christophe Vanherck / Annelies Janssens / Stéphane A H Spieser / Damien Marchand / Robbe Roelens / Patrick Chaltin / Arnaud Marchand / Joris Vriens / Thomas Voets / Janine D Brunner /
Abstract: The transient receptor potential melastatin 3 (TRPM3) channel is a key mediator of peripheral pain signaling, and pathogenic mutations in TRPM3 are linked to neurodevelopmental delay and epilepsy. ...The transient receptor potential melastatin 3 (TRPM3) channel is a key mediator of peripheral pain signaling, and pathogenic mutations in TRPM3 are linked to neurodevelopmental delay and epilepsy. Despite the therapeutic promise of TRPM3 modulators, the molecular mechanisms by which ligands modulate channel gating remain poorly understood. Here, we combine cryo-electron microscopy (cryo-EM) with functional analyses to characterize a promiscuous ligand-binding pocket formed by transmembrane helices S1-S4. This pocket accommodates several chemically diverse plant-derived and synthetic agonists and antagonists. We show stereoselectivity of TRPM3 for the (R)-enantiomer of the flavonoid antagonist isosakuranetin and the (R)-enantiomer of the synthetic agonist CIM0216. Mutations within this pocket-including variants identified in patients -alter ligand affinity and, in some cases, invert the functional outcome of ligand binding. These findings reveal the stereoselectivity and functional plasticity of the TRPM3 ligand-binding pocket, highlighting how subtle changes in the molecular interactions can produce divergent effects on channel gating, with important ramifications for TRPM3-targeted drug development and therapy.
History
DepositionNov 17, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 11, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2026Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.1Aug 26, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: MKIAA1616 protein
B: MKIAA1616 protein
C: MKIAA1616 protein
D: MKIAA1616 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)655,02320
Polymers647,8534
Non-polymers7,17016
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
MKIAA1616 protein


Mass: 161963.250 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Trpm3, mKIAA1616 / Variant: alpha 2 / Plasmid: pcDNA5/TO / Cell line (production host): Flp-In T-REx 293 / Production host: Homo sapiens (human) / References: UniProt: Q69ZE8
#2: Chemical
ChemComp-A1D6M / 1-[2,4-bis(oxidanyl)phenyl]-2-(4-methoxyphenyl)ethanone / ONONETIN


Mass: 258.269 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H14O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-3PH / 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / PHOSPHATIDIC ACID


Mass: 704.998 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C39H77O8P
#4: Chemical
ChemComp-YUV / (25R)-14beta,17beta-spirost-5-en-3beta-ol


Mass: 414.621 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C27H42O3
Has ligand of interestY
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: Tetrameric assembly of mouse TRPM3 alpha 2 with inhibitor Ononetin
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.161 MDa / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human) / Strain: Flp-In T-REx 293
Buffer solutionpH: 7.5
Details: 10 mM Hepes pH 7.5, 150 mM NaCl, 0.063% Glycodiosgenin, 10 uM Ononetin
Buffer component
IDConc.NameFormulaBuffer-ID
110 mMHepesC8H17N2NaO4S1
2150 mMSodium chlorideNaCl1
30.0063 %GlycodiosgeninC56H92O251
410 uMOnonetinC15H14O41
SpecimenConc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 279.15 K / Details: GP2

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Electron microscopy imaging

MicroscopyModel: JEOL CRYO ARM 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1000 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 62 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCv4.4.1+particle selection
2SerialEM4.1.8image acquisition
9PHENIX1.21-5207model refinement
13PHENIX3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 309057 / Symmetry type: POINT
RefinementHighest resolution: 2.61 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00434496
ELECTRON MICROSCOPYf_angle_d0.60946672
ELECTRON MICROSCOPYf_dihedral_angle_d7.9744832
ELECTRON MICROSCOPYf_chiral_restr0.0415196
ELECTRON MICROSCOPYf_plane_restr0.0055780

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