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- EMDB-48816: Cryo-EM structure of rabbit TRPM3 in complex with primidone in re... -

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Basic information

Entry
Database: EMDB / ID: EMD-48816
TitleCryo-EM structure of rabbit TRPM3 in complex with primidone in resting state at 18 degrees Celsius
Map data
Sample
  • Organelle or cellular component: tetramer of TRPM3
    • Protein or peptide: TRPM3
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: primidone
KeywordsTRPM3 / ion channel / membrane protein
Biological speciesOryctolagus cuniculus (rabbit)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.93 Å
AuthorsKumar S / Lu W / Du J
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL153219 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS112363 United States
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Structural basis for agonist and heat activation of nociceptor TRPM3.
Authors: Sushant Kumar / Fei Jin / Sung Jin Park / Wooyoung Choi / Sarah I Keuning / Richard P Massimino / Simon Vu / Wei Lü / Juan Du /
Abstract: Detecting noxious heat is vital for survival, triggering protective pain responses. The TRPM3 channel is a key nociceptor and a promising therapeutic target for pain and neurological disorders. Here ...Detecting noxious heat is vital for survival, triggering protective pain responses. The TRPM3 channel is a key nociceptor and a promising therapeutic target for pain and neurological disorders. Here we show that the rabbit TRPM3 is intrinsically dynamic, with its intracellular domain (ICD) sampling both resting and activated states, but favoring the resting state in the absence of stimulation. We reveal that heat and the synthetic agonist CIM0216 shift the equilibrium toward activation by inducing a similar ICD rearrangement. Mutations that facilitate ICD movement enhance sensitivity to both thermal and chemical stimuli, underscoring the central role of the ICD in channel gating. We also show that the antagonist primidone binds the same site as CIM0216 in the S1-S4 domain but inhibits channel activation. This study provides a structural framework for a mechanistic understanding of thermal and chemical gating of TRPM3 and for guiding the rational design of TRPM3-targeted analgesics and neurotherapeutics.
History
DepositionJan 26, 2025-
Header (metadata) releaseDec 17, 2025-
Map releaseDec 17, 2025-
UpdateDec 17, 2025-
Current statusDec 17, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48816.png

Downloads & links

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Map

FileDownload / File: emd_48816.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 384 pix.
= 317.184 Å		0.83 Å/pix.
x 384 pix.
= 317.184 Å		0.83 Å/pix.
x 384 pix.
= 317.184 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.826 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.004
Minimum - Maximum-0.0037333982 - 0.014689458
Average (Standard dev.)0.000077413875 (±0.00067482784)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 317.184 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_48816_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

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Histogram (log scale)

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Half map: #1

Fileemd_48816_half_map_2.map
Projections & Slices
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Sample components

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Entire : tetramer of TRPM3

EntireName: tetramer of TRPM3
Components
  • Organelle or cellular component: tetramer of TRPM3
    • Protein or peptide: TRPM3
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: primidone

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Supramolecule #1: tetramer of TRPM3

SupramoleculeName: tetramer of TRPM3 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Oryctolagus cuniculus (rabbit)

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Macromolecule #1: TRPM3

MacromoleculeName: TRPM3 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Molecular weightTheoretical: 150.840328 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MCWKGVIPGE LVDPVAGREG TQRRFRAQKS WIERAFYKRE CVHIIPSTKD PHRCCCGRLI GQHVGLTPSI SVLQNEKNES RLSRNDIQS EKWSISKHTQ LSPTDAFGTI EFQGGGHSNK AMYVRVSFDT KPDLLLHLMT KEWQLELPKL LISVHGGLQN F ELQPKLKQ ...String:
MCWKGVIPGE LVDPVAGREG TQRRFRAQKS WIERAFYKRE CVHIIPSTKD PHRCCCGRLI GQHVGLTPSI SVLQNEKNES RLSRNDIQS EKWSISKHTQ LSPTDAFGTI EFQGGGHSNK AMYVRVSFDT KPDLLLHLMT KEWQLELPKL LISVHGGLQN F ELQPKLKQ VFGKGLIKAA MTTGAWIFTG GVNTGVIRHV GDALKDHASK SRGKICTIGI APWGIVENQE DLIGRDVVRP YQ TMSNPMS KLTVLNSMHS HFILADNGTT GKYGAEVKLR RQLEKHISLQ KINTRIGQGV PVVALIVEGG PNVISIVLEY LRD TPPVPV VVCDGSGRAS DILAFGHKYS EEGGLINESL RDQLLVTIQK TFTYTRTQAQ HLFIILMECM KKKELITVFR MGSE GHQDI DLAILTALLK GANASAPDQL SLALAWNRVD IARSQIFIYG QQWPVGSLEQ AMLDALVLDR VDFVKLLIEN GVSMH RFLT ISRLEELYNT RHGPSNTLYH LVRDVKKREY PGFGWIYFKG NLPPDYRISL IDIGLVIEYL MGGAYRCNYT RKRFRT LYH NLFGPKRPKA LKLLGMEDDI PLRRGRKTTK KREEEVDIDL DDPEINHFPF PFHELMVWAV LMKRQKMALF FWQHGEE AM AKALVACKLC KAMAHEASEN DMVDDISQEL NHNSRDFGQL AVELLDQSYK QDEQLAMKLL TYELKNWSNA TCLQLAVA A KHRDFIAHTC SQMLLTDMWM GRLRMRKNSG LKVILGILLP PSILSLEFKN KDDMPYMTQA QEIHLQEKEP EEPEKPTKE KDEEDMELTA MLGRNNGESS RKKDEEEVQS RHRLIPLGRK IYEFYNAPIV KFWFYTLAYI GYLMLFNYIV LVKMERWPST QEWIVISYI FTLGIEKMRE ILMSEPGKLL QKVKVWLQEY WNVTDLIAIL LFSVGMILRL QDQPFRSDGR VIYCVNIIYW Y IRLLDIFG VNKYLGPYVM MIGKMMIDMM YFVIIMLVVL MSFGVARQAI LFPNEEPSWK LAKNIFYMPY WMIYGEVFAD QI DPPCGQN ETREDGKIIQ LPPCKTGAWI VPAIMACYLL VANILLVNLL IAVFNNTFFE VKSISNQVWK FQRYQLIMTF HER PVLPPP LIIFSHMTMI FQHLCCRWRK HESDPDERDY GLKLFITDDE LKKVHDFEEQ CIEEYFREKD DRFNSSNDER IRVT SERVE NMSMRLEEVN EREHSMKASL QTVDIRLAQL EDLIGRMATA LERLTGVERA ESNKIRSRTS SDCTDAAYIV RQSSF NSQE GNTFKLQESI DPAEHPFYSV FE

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Macromolecule #2: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 2 / Number of copies: 24 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #3: primidone

MacromoleculeName: primidone / type: ligand / ID: 3 / Number of copies: 4 / Formula: A1AIA
Molecular weightTheoretical: 218.252 Da

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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

Concentration8 mg/mL
BufferpH: 7.5
Details: 20 mM Hepes pH 7.5, 150 mM NaCl, 0.001 % LMNG/CHS, 10 mM beta-mercaptoethanol, 5 mM EDTA
GridModel: Quantifoil R2/1 / Material: GOLD / Mesh: 300
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 1.1 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 419231
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: PROJECTION MATCHING

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