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- PDB-9o86: Cryo-EM structure of CIM0216-bound rabbit TRPM3 having 3 resting ... -

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Basic information

Entry
Database: PDB / ID: 9o86
TitleCryo-EM structure of CIM0216-bound rabbit TRPM3 having 3 resting and 1 activated subunits at 18 degrees Celsius
ComponentsTRPM3
KeywordsMEMBRANE PROTEIN / TRPM3 / ion channel
Function / homology:
Function and homology information
Biological speciesOryctolagus cuniculus (rabbit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.11 Å
AuthorsKumar, S. / Lu, W. / Du, J.
Funding support United States, 2items
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
DepositionApr 15, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 17, 2025Provider: repository / Type: Initial release
Revision 1.0Dec 17, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 17, 2025Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Dec 17, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 17, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 17, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 17, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: TRPM3
A: TRPM3
D: TRPM3
B: TRPM3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)604,7518
Polymers603,3614
Non-polymers1,3904
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
TRPM3


Mass: 150840.328 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#2: Chemical
ChemComp-A1AIB / (2S)-2-(3,4-dihydroquinolin-1(2H)-yl)-N-(5-methyl-1,2-oxazol-3-yl)-2-phenylacetamide


Mass: 347.410 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H21N3O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: rabbit TRPM3 in complex with agonist CIM0216 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Details: 20 mM Hepes pH 7.5, 150 mM NaCl, 0.001 % LMNG/CHS, 10 mM beta-mercaptoethanol, 5 mM EDTA
SpecimenConc.: 8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 291.15 K

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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: BRIGHT FIELD / Nominal defocus max: 1400 nm / Nominal defocus min: 1100 nm
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
2PHENIX1.21.2_5419model refinement
11RELION5final Euler assignment
12RELION5classification
13RELION53D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.11 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 29177 / Symmetry type: POINT
RefinementHighest resolution: 4.11 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.02131199
ELECTRON MICROSCOPYf_angle_d1.24742490
ELECTRON MICROSCOPYf_dihedral_angle_d8.3054528
ELECTRON MICROSCOPYf_chiral_restr0.0634945
ELECTRON MICROSCOPYf_plane_restr0.0115388

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