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- PDB-9pwf: Menthol-bound mouse TRPM8-I846V in complex with PIP2 in an interm... -

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Basic information

Entry
Database: PDB / ID: 9pwf
TitleMenthol-bound mouse TRPM8-I846V in complex with PIP2 in an intermediate (C2M, 20C) state
ComponentsTransient receptor potential cation channel subfamily M member 8
KeywordsMEMBRANE PROTEIN / TRPM8 / Menthol / Cold / channel opening
Function / homology
Function and homology information


TRP channels / thermoception / ligand-gated calcium channel activity / response to temperature stimulus / plasma membrane raft / monoatomic ion channel activity / response to cold / intracellular calcium ion homeostasis / calcium channel activity / calcium ion transmembrane transport ...TRP channels / thermoception / ligand-gated calcium channel activity / response to temperature stimulus / plasma membrane raft / monoatomic ion channel activity / response to cold / intracellular calcium ion homeostasis / calcium channel activity / calcium ion transmembrane transport / calcium ion transport / positive regulation of cold-induced thermogenesis / membrane raft / external side of plasma membrane / membrane / identical protein binding / plasma membrane
Similarity search - Function
TRPM, SLOG domain / : / : / SLOG in TRPM / TRPM2-like domain / : / Calcium channel YVC1-like, C-terminal
Similarity search - Domain/homology
Chem-PIO / : / Transient receptor potential cation channel subfamily M member 8
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsLee, H.J. / Lee, S.Y.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R35NS097241 United States
National Institutes of Health/National Eye Institute (NIH/NEI)R01EY031698 United States
CitationJournal: Nat Commun / Year: 2026
Title: Molecular basis for cold and menthol sensing by mammalian TRPM8.
Authors: Hyuk-Joon Lee / Cheon-Gyu Park / Justin G Fedor / Wyatt A Peele / Mario J Borgnia / Seok-Yong Lee /
Abstract: The transient receptor potential melastatin member 8 (TRPM8) is a polymodal ion channel that senses cold and menthol in mammals. Despite prior structural studies, the mechanisms by which cold and ...The transient receptor potential melastatin member 8 (TRPM8) is a polymodal ion channel that senses cold and menthol in mammals. Despite prior structural studies, the mechanisms by which cold and menthol activate TRPM8 remain unresolved. Here, we present cryo-EM structures and extensive functional analyses to reveal cold- and menthol-dependent activation mechanisms. We observe that cold-sensing residues are widespread and that snapshots of cooling-dependent opening reveal dramatic pore rearrangement which suggest a mechanism for cold sensing. Menthol binds dynamically to drive channel activation toward a common gate with cold, but with specific outer pore conformations. Finally, we show how TRPM8 integrates cold and menthol modalities through overlapping but non-identical networks, revealing a coldspot that is central to cold activation of TRPM8 and is the location of allyl isothiocyanate (AITC) binding. These findings enhance our understanding of the molecular basis of physically and chemically induced cool sensation in mammals.
History
DepositionAug 4, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 7, 2026Provider: repository / Type: Initial release
Revision 1.0Oct 7, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily M member 8
B: Transient receptor potential cation channel subfamily M member 8
C: Transient receptor potential cation channel subfamily M member 8
D: Transient receptor potential cation channel subfamily M member 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)514,97712
Polymers511,3664
Non-polymers3,6118
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 8 / Long transient receptor potential channel 6 / LTrpC-6 / LTrpC6 / Transient receptor potential p8 / Trp-p8


Mass: 127841.469 Da / Num. of mol.: 4 / Mutation: I846V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Trpm8, Ltrpc6, Trpp8 / Production host: Homo sapiens (human) / References: UniProt: Q8R4D5
#2: Chemical
ChemComp-PIO / [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate / dioctanoyl l-alpha-phosphatidyl-d-myo-inositol 4,5-diphosphate


Mass: 746.566 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H49O19P3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-XUQ / (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-ol / L-menthol


Mass: 156.265 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H20O / Feature type: SUBJECT OF INVESTIGATION
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 complex of mouse TRPM8-I846V in domain-swapped architecture
Type: COMPLEX
Details: Menthol-bound mouse TRPM8-I846V in complex with PIP2 in an intermediate (C2M) state
Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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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: 2000 nm / Nominal defocus min: 750 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 75451 / Symmetry type: POINT
RefinementHighest resolution: 3.1 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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