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- EMDB-74129: Human TRPM8 (wild-type) semi-swapped structure, calcium-free, 4 d... -

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Entry
Database: EMDB / ID: EMD-74129
TitleHuman TRPM8 (wild-type) semi-swapped structure, calcium-free, 4 degress Celsius, determined using cell vesicles
Map data
Sample
  • Complex: Homotetrameric complex of human TRPM8 determined in cell-derived vesicles.
KeywordsTRPM8 / transient receptor potential melastatin 8 / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.44 Å
AuthorsChoi KY / Lin X / Cheng Y / Julius D
Funding support United States, 3 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R35NS105038 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM140847 United States
CitationJournal: Nature / Year: 2026
Title: Structural energetics of cold sensitivity.
Authors: Kevin Y Choi / Xiaoxuan Lin / Yifan Cheng / David Julius /
Abstract: Thermosensitive transient receptor potential (TRP) ion channels enable somatosensory nerve fibres to detect changes in our thermal environment over a wide physiologic range. In mammals, the menthol ...Thermosensitive transient receptor potential (TRP) ion channels enable somatosensory nerve fibres to detect changes in our thermal environment over a wide physiologic range. In mammals, the menthol receptor, TRPM8, is activated by temperatures below approximately 26 °C and is essential for the perception of cold or chemical cooling agents. A fascinating, yet still unachieved goal is to elucidate mechanisms, both structural and thermodynamic, whereby TRPM8 or other thermosensitive channels are gated by changes in ambient temperature. Recent studies using cryogenic electron microscopy have attempted to address this challenging question but are limited by difficulties in visualizing temperature-evoked conformational sub-states or assessing the energetic landscape governing gating transitions. Here we close this gap by combining cryogenic electron microscopy with hydrogen-deuterium exchange mass spectrometry to elucidate a mechanism for cold-evoked activation of TRPM8. First, we visualize TRPM8 channels in cellular membranes, where bona fide menthol- and cold-evoked open states are captured. We also identify a new 'semi-swapped' architecture in which interdigitation of channel sub-units is rearranged substantially following repositioning of the S6 transmembrane helix and elements of the pore region. We then use hydrogen-deuterium exchange mass spectrometry to pinpoint the pore and TRP helices as the regions exhibiting the greatest stimulus-evoked energetic changes that drive channel gating. Specifically, cold-evoked stabilization of the outer pore region repositions the pore lining S6 transmembrane helix while enabling binding of a regulatory lipid to stabilize the open channel. Structural mechanisms associated with activation are validated by comparison of human TRPM8 with the menthol-sensitive but relatively cold-insensitive avian orthologue. We propose a free energy landscape and conformational pathway whereby cold or cooling agents activate this thermosensory receptor.
History
DepositionDec 1, 2025-
Header (metadata) releaseApr 8, 2026-
Map releaseApr 8, 2026-
UpdateApr 8, 2026-
Current statusApr 8, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_74129.png

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Map

FileDownload / File: emd_74129.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 320 pix.
= 262.048 Å		0.82 Å/pix.
x 320 pix.
= 262.048 Å		0.82 Å/pix.
x 320 pix.
= 262.048 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8189 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.4089435 - 0.7684933
Average (Standard dev.)0.004213554 (±0.039992128)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 262.048 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_74129_additional_1.map
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Half map: #1

Fileemd_74129_half_map_1.map
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Half map: #2

Fileemd_74129_half_map_2.map
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Sample components

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Entire : Homotetrameric complex of human TRPM8 determined in cell-derived ...

EntireName: Homotetrameric complex of human TRPM8 determined in cell-derived vesicles.
Components
  • Complex: Homotetrameric complex of human TRPM8 determined in cell-derived vesicles.

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Supramolecule #1: Homotetrameric complex of human TRPM8 determined in cell-derived ...

SupramoleculeName: Homotetrameric complex of human TRPM8 determined in cell-derived vesicles.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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: 7.4
Component:
ConcentrationFormulaName
300.0 mMKClpotassium chloride
20.0 mMC8H18N2O4SHEPES
0.5 mMC13H17F13NO4PFos-Choline-8, Fluorinated
GridModel: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: CONTINUOUS
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 3 / Number real images: 74792 / Average exposure time: 2.0 sec. / Average electron dose: 47.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 105000
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: 2552130
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Details: Initial model generated ab initio from screening dataset and used for subsequent refinement.
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.44 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4) / Number images used: 70324
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4)

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