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- EMDB-44102: Cryo-EM structure of the mouse TRPM3 alpha 2 channel in complex w... -

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Basic information

Entry
Database: EMDB / ID: EMD-44102
TitleCryo-EM structure of the mouse TRPM3 alpha 2 channel in complex with the neurosteroid pregnenolone sulfate and the synthetic agonist CIM 0216
Map dataThe final full map with global sharpening at B-factor -25
Sample
  • Complex: Transient receptor potential cation channel subfamily M member 3
    • Protein or peptide: Transient receptor potential cation channel, subfamily M, member 3
  • Ligand: (2S)-2-(3,4-dihydroquinolin-1(2H)-yl)-N-(5-methyl-1,2-oxazol-3-yl)-2-phenylacetamide
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
  • Ligand: Pregnenolone sulfate
KeywordsTransient receptor potential channel / TRPM3 / neurosteroid / pregnenolone sulfate / neurodevelopmental disorders / anticonvulsant / primidone / neurological disorders / nociception / analgesic / TRANSPORT PROTEIN
Function / homology
Function and homology information


zinc ion transmembrane transporter activity / zinc ion transmembrane transport / temperature-gated ion channel activity / sodium ion transport / monoatomic cation transport / monoatomic cation channel activity / phosphatidylinositol-4,5-bisphosphate binding / calcium ion transmembrane transport / calcium channel activity / G-protein beta/gamma-subunit complex binding ...zinc ion transmembrane transporter activity / zinc ion transmembrane transport / temperature-gated ion channel activity / sodium ion transport / monoatomic cation transport / monoatomic cation channel activity / phosphatidylinositol-4,5-bisphosphate binding / calcium ion transmembrane transport / calcium channel activity / G-protein beta/gamma-subunit complex binding / protein homotetramerization / calmodulin binding / plasma membrane
Similarity search - Function
TRPM, tetramerisation domain / TRPM, tetramerisation domain superfamily / Tetramerisation domain of TRPM / TRPM, SLOG domain / : / SLOG in TRPM / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily M member 3
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.82 Å
AuthorsYin Y / Park CG / Feng S / Zhang F / Guan Z / Sharma K / Borgnia MJ / Im W / Lee S-Y
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) United States
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Molecular basis of neurosteroid and anticonvulsant regulation of TRPM3.
Authors: Ying Yin / Cheon-Gyu Park / Shasha Feng / Ziqiang Guan / Hyuk-Joon Lee / Feng Zhang / Kedar Sharma / Mario J Borgnia / Wonpil Im / Seok-Yong Lee /
Abstract: Transient receptor potential channel subfamily M member 3 (TRPM3) is a Ca-permeable cation channel activated by the neurosteroid pregnenolone sulfate (PregS) or heat, serving as a nociceptor in the ...Transient receptor potential channel subfamily M member 3 (TRPM3) is a Ca-permeable cation channel activated by the neurosteroid pregnenolone sulfate (PregS) or heat, serving as a nociceptor in the peripheral sensory system. Recent discoveries of autosomal dominant neurodevelopmental disorders caused by gain-of-function mutations in TRPM3 highlight its role in the central nervous system. Notably, the TRPM3 inhibitor primidone, an anticonvulsant, has proven effective in treating patients with TRPM3-linked neurological disorders and in mouse models of thermal nociception. However, our understanding of neurosteroids, inhibitors and disease mutations on TRPM3 is limited. Here we present cryogenic electron microscopy structures of the mouse TRPM3 in complex with cholesteryl hemisuccinate, primidone and PregS with the synthetic agonist CIM 0216. Our studies identify the binding sites for the neurosteroid, synthetic agonist and inhibitor and offer insights into their effects and disease mutations on TRPM3 gating, aiding future drug development.
History
DepositionMar 14, 2024-
Header (metadata) releaseJan 22, 2025-
Map releaseJan 22, 2025-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44102.png

Downloads & links

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Map

FileDownload / File: emd_44102.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe final full map with global sharpening at B-factor -25
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 320 pix.
= 345.6 Å		1.08 Å/pix.
x 320 pix.
= 345.6 Å		1.08 Å/pix.
x 320 pix.
= 345.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.43581414 - 0.93168133
Average (Standard dev.)0.0065310406 (±0.043932322)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 345.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A

Fileemd_44102_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_44102_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Transient receptor potential cation channel subfamily M member 3

EntireName: Transient receptor potential cation channel subfamily M member 3
Components
  • Complex: Transient receptor potential cation channel subfamily M member 3
    • Protein or peptide: Transient receptor potential cation channel, subfamily M, member 3
  • Ligand: (2S)-2-(3,4-dihydroquinolin-1(2H)-yl)-N-(5-methyl-1,2-oxazol-3-yl)-2-phenylacetamide
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
  • Ligand: Pregnenolone sulfate

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Supramolecule #1: Transient receptor potential cation channel subfamily M member 3

SupramoleculeName: Transient receptor potential cation channel subfamily M member 3
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Transient receptor potential cation channel, subfamily M, member 3

MacromoleculeName: Transient receptor potential cation channel, subfamily M, member 3
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 198.674297 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGKKWRDAGE LERGCSDRED SAESRRRSRS ASRGRFAESW KRLSSKQGST KRSGLPAQQT PAQKSWIERA FYKRECVHII PSTKDPHRC CCGRLIGQHV GLTPSISVLQ NEKNESRLSR NDIQSEKWSI SKHTQLSPTD AFGTIEFQGG GHSNKAMYVR V SFDTKPDL ...String:
MGKKWRDAGE LERGCSDRED SAESRRRSRS ASRGRFAESW KRLSSKQGST KRSGLPAQQT PAQKSWIERA FYKRECVHII PSTKDPHRC CCGRLIGQHV GLTPSISVLQ NEKNESRLSR NDIQSEKWSI SKHTQLSPTD AFGTIEFQGG GHSNKAMYVR V SFDTKPDL LLHLMTKEWQ LELPKLLISV HGGLQNFELQ PKLKQVFGKG LIKAAMTTGA WIFTGGVNTG VIRHVGDALK DH ASKSRGK ICTIGIAPWG IVENQEDLIG RDVVRPYQTM SNPMSKLTVL NSMHSHFILA DNGTTGKYGA EVKLRRQLEK HIS LQKINT RIGQGVPVVA LIVEGGPNVI SIVLEYLRDT PPVPVVVCDG SGRASDILAF GHKYSEEGGL INESLRDQLL VTIQ KTFTY TRTQAQHLFI ILMECMKKKE LITVFRMGSE GHQDIDLAIL TALLKGANAS APDQLSLALA WNRVDIARSQ IFIYG QQWP VGSLEQAMLD ALVLDRVDFV KLLIENGVSM HRFLTISRLE ELYNTRHGPS NTLYHLVRDV KKGNLPPDYR ISLIDI GLV IEYLMGGAYR CNYTRKRFRT LYHNLFGPKR PKALKLLGME DDIPLRRGRK TTKKREEEVD IDLDDPEINH FPFPFHE LM VWAVLMKRQK MALFFWQHGE EAMAKALVAC KLCKAMAHEA SENDMVDDIS QELNHNSRDF GQLAVELLDQ SYKQDEQL A MKLLTYELKN WSNATCLQLA VAAKHRDFIA HTCSQMLLTD MWMGRLRMRK NSGLKVILGI LLPPSILSLE FKNKDDMPY MTQAQEIHLQ EKEPEEPEKP TKEKDEEDME LTAMLGRSNG ESSRKKDEEE VQSRHRLIPV GRKIYEFYNA PIVKFWFYTL AYIGYLMLF NYIVLVKMER WPSTQEWIVI SYIFTLGIEK MREILMSEPG KLLQKVKVWL QEYWNVTDLI AILLFSVGMI L RLQDQPFR SDGRVIYCVN IIYWYIRLLD IFGVNKYLGP YVMMIGKMMI DMMYFVIIML VVLMSFGVAR QAILFPNEEP SW KLAKNIF YMPYWMIYGE VFADQIDPPC GQNETREDGK TIQLPPCKTG AWIVPAIMAC YLLVANILLV NLLIAVFNNT FFE VKSISN QVWKFQRYQL IMTFHERPVL PPPLIIFSHM TMIFQHVCCR WRKHESDQDE RDYGLKLFIT DDELKKVHDF EEQC IEEYF REKDDRFNSS NDERIRVTSE RVENMSMRLE EVNEREHSMK ASLQTVDIRL AQLEDLIGRM ATALERLTGL ERAES NKIR SRTSSDCTDA AYIVRQSSFN SQEGNTFKLQ ESIDPAGEET ISPTSPTLMP RMRSHSFYSV NVKDKGGIEK LESIFK ERS LSLHRATSSH SVAKEPKAPA APANTLAIVP DSRRPSSCID IYVSAMDELH CDIEPLDNSM NILGLGEPSF SALAPST TP SSSAYATLAP TDRPPSRSID FEDLTSMDTR SFSSDYTHLP ECQNPWDTDP PTYHTIERSK SSRYLATTPF LLEEAPIV K SHSFMFSPSR SYYANFGVPV KTAEYTSITD CIDTRCVNAP QAIADRATFP GGLGDKVEDL SCCHPEREAE LSHPSSDSE ENEARGQRAA NPISSQEAEN ADRTLSNNIT VPKIERANSY SAEEPNVPYA HTRKSFSISD KLDRQRNTAS LRNPFQRSKS SKPEGRGDS LSMRRLSRTS AFHSFESKHN SNSLEVLFQG PDYKDDDDKA HHHHHHHHHH

UniProtKB: Transient receptor potential cation channel subfamily M member 3

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Macromolecule #2: (2S)-2-(3,4-dihydroquinolin-1(2H)-yl)-N-(5-methyl-1,2-oxazol-3-yl...

MacromoleculeName: (2S)-2-(3,4-dihydroquinolin-1(2H)-yl)-N-(5-methyl-1,2-oxazol-3-yl)-2-phenylacetamide
type: ligand / ID: 2 / Number of copies: 4 / Formula: A1AIB
Molecular weightTheoretical: 347.41 Da

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Macromolecule #3: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyl...

MacromoleculeName: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
type: ligand / ID: 3 / Number of copies: 4 / Formula: 6OU
Molecular weightTheoretical: 717.996 Da
Chemical component information

ChemComp-6OU:
[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / phospholipid*YM

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Macromolecule #4: Pregnenolone sulfate

MacromoleculeName: Pregnenolone sulfate / type: ligand / ID: 4 / Number of copies: 4 / Formula: A8W
Molecular weightTheoretical: 396.541 Da
Chemical component information

ChemComp-A8W:
Pregnenolone sulfate / antidepressant*YM

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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
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 2 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 8390 / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 81000
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

Particle selectionNumber selected: 3055604
CTF correctionSoftware: (Name: Gctf, RELION) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Details: The high-resolution 3D reconstruction from another dataset of this study was low-pass filtered to 30-angstrom and used as an initial model.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.82 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 25649
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9b2a:
Cryo-EM structure of the mouse TRPM3 alpha 2 channel in complex with the neurosteroid pregnenolone sulfate and the synthetic agonist CIM 0216

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