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- EMDB-72557: The cold-intermediate state (C2M, 4C), menthol-bound mouse TRPM8-... -

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Basic information

Entry
Database: EMDB / ID: EMD-72557
TitleThe cold-intermediate state (C2M, 4C), menthol-bound mouse TRPM8-I846V in complex with AITC and PIP2
Map datasharpened_map
Sample
  • Complex: Tetrameric complex of mouse TRPM8-I846V in domain-swapped architecture
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 8
  • Ligand: [(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
  • Ligand: (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-ol
KeywordsTRPM8 / Cold / Menthol / Channel opening / MEMBRANE PROTEIN
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
Transient receptor potential cation channel subfamily M member 8
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLee HJ / Lee SY
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)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
DepositionSep 8, 2025-
Header (metadata) releaseOct 7, 2026-
Map releaseOct 7, 2026-
UpdateOct 7, 2026-
Current statusOct 7, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72557.png

Downloads & links

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Map

FileDownload / File: emd_72557.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened_map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 360 pix.
= 303.48 Å		0.84 Å/pix.
x 360 pix.
= 303.48 Å		0.84 Å/pix.
x 360 pix.
= 303.48 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.843 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.46
Minimum - Maximum-1.3662287 - 2.8500082
Average (Standard dev.)0.024110842 (±0.08645963)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 303.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: non sharpened map

Fileemd_72557_additional_1.map
Annotationnon_sharpened_map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_72557_half_map_1.map
Annotationhalf_map_B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_72557_half_map_2.map
Annotationhalf_map_A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Tetrameric complex of mouse TRPM8-I846V in domain-swapped architecture

EntireName: Tetrameric complex of mouse TRPM8-I846V in domain-swapped architecture
Components
  • Complex: Tetrameric complex of mouse TRPM8-I846V in domain-swapped architecture
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 8
  • Ligand: [(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
  • Ligand: (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-ol

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Supramolecule #1: Tetrameric complex of mouse TRPM8-I846V in domain-swapped architecture

SupramoleculeName: Tetrameric complex of mouse TRPM8-I846V in domain-swapped architecture
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: The cold-intermediate state (C2M, 4C), menthol-bound mouse TRPM8-I846V in complex with AITC and PIP2
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Transient receptor potential cation channel subfamily M member 8

MacromoleculeName: Transient receptor potential cation channel subfamily M member 8
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 127.841469 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSFEGARLSM RSRRNGTMGS TRTLYSSVSR STDVSYSDSD LVNFIQANFK KRECVFFTRD SKAMENICKC GYAQSQHIEG TQINQNEKW NYKKHTKEFP TDAFGDIQFE TLGKKGKYLR LSCDTDSETL YELLTQHWHL KTPNLVISVT GGAKNFALKP R MRKIFSRL ...String:
MSFEGARLSM RSRRNGTMGS TRTLYSSVSR STDVSYSDSD LVNFIQANFK KRECVFFTRD SKAMENICKC GYAQSQHIEG TQINQNEKW NYKKHTKEFP TDAFGDIQFE TLGKKGKYLR LSCDTDSETL YELLTQHWHL KTPNLVISVT GGAKNFALKP R MRKIFSRL IYIAQSKGAW ILTGGTHYGL MKYIGEVVRD NTISRNSEEN IVAIGIAAWG MVSNRDTLIR SCDDEGHFSA QY IMDDFTR DPLYILDNNH THLLLVDNGC HGHPTVEAKL RNQLEKYISE RTSQDSNYGG KIPIVCFAQG GGRETLKAIN TSV KSKIPC VVVEGSGQIA DVIASLVEVE DVLTSSMVKE KLVRFLPRTV SRLPEEEIES WIKWLKEILE SSHLLTVIKM EEAG DEIVS NAISYALYKA FSTNEQDKDN WNGQLKLLLE WNQLDLASDE IFTNDRRWES ADLQEVMFTA LIKDRPKFVR LFLEN GLNL QKFLTNEVLT ELFSTHFSTL VYRNLQIAKN SYNDALLTFV WKLVANFRRS FWKEDRSSRE DLDVELHDAS LTTRHP LQA LFIWAILQNK KELSKVIWEQ TKGCTLAALG ASKLLKTLAK VKNDINAAGE SEELANEYET RAVELFTECY SNDEDLA EQ LLVYSCEAWG GSNCLELAVE ATDQHFIAQP GVQNFLSKQW YGEISRDTKN WKIILCLFII PLVGCGLVSF RKKPIDKH K KLLWYYVAFF TSPFVVFSWN VVFYIAFLLL FAYVLLMDFH SVPHTPELIL YALVFVLFCD EVRQWYMNGV NYFTDLWNV MDTLGLFYFI AGIVFRLHSS NKSSLYSGRV IFCLDYIIFT LRLIHVFTVS RNLGPKIIML QRMLIDVFFF LFLFAVWMVA FGVARQGIL RQNEQRWRWI FRSVIYEPYL AMFGQVPSDV DSTTYDFSHC TFSGNESKPL CVELDEHNLP RFPEWITIPL V CIYMLSTN ILLVNLLVAM FGYTVGIVQE NNDQVWKFQR YFLVQEYCNR LNIPFPFVVF AYFYMVVKKC FKCCCKEKNM ES NACCFRN EDNETLAWEG VMKENYLVKI NTKANDNSEE MRHRFRQLDS KLNDLKSLLK EIANNIK

UniProtKB: Transient receptor potential cation channel subfamily M member 8

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Macromolecule #2: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(o...

MacromoleculeName: [(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
type: ligand / ID: 2 / Number of copies: 4 / Formula: PIO
Molecular weightTheoretical: 746.566 Da
Chemical component information

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

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Macromolecule #3: (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-ol

MacromoleculeName: (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-ol / type: ligand / ID: 3 / Number of copies: 4 / Formula: XUQ
Molecular weightTheoretical: 156.265 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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.7000000000000001 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: EMDB MAP
EMDB ID:

71917

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 47522
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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