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- EMDB-71394: Avian TRPM8 (Parus major) desensitized, fully-swapped, ligand-fre... -

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Basic information

Entry
Database: EMDB / ID: EMD-71394
TitleAvian TRPM8 (Parus major) desensitized, fully-swapped, ligand-free structure resolved in cell vesicles using cryo-EM
Map data
Sample
  • Complex: Homotetrameric complex of Parus major TRPM8 determined in a cell-derived vesicles.
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 8
KeywordsTRPM8 / transient receptor potential melastatin 8 / MEMBRANE PROTEIN / Parus major
Function / homology
Function and homology information


ligand-gated calcium channel activity / plasma membrane
Similarity search - Function
TRPM, SLOG domain / : / : / SLOG in TRPM / TRPM2-like domain / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily M member 8
Similarity search - Component
Biological speciesParus major (Great Tit)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 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
DepositionJun 23, 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_71394.png

Downloads & links

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Map

FileDownload / File: emd_71394.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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Others
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

Projections

Slices (1/3)

Slices (1/2)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8189 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.008
Minimum - Maximum-0.012346207 - 0.031503372
Average (Standard dev.)0.00014115697 (±0.0021361217)
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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Half map: #1

Fileemd_71394_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_71394_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Homotetrameric complex of Parus major TRPM8 determined in a cell-...

EntireName: Homotetrameric complex of Parus major TRPM8 determined in a cell-derived vesicles.
Components
  • Complex: Homotetrameric complex of Parus major TRPM8 determined in a cell-derived vesicles.
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 8

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Supramolecule #1: Homotetrameric complex of Parus major TRPM8 determined in a cell-...

SupramoleculeName: Homotetrameric complex of Parus major TRPM8 determined in a cell-derived vesicles.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Parus major (Great Tit)

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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: Parus major (Great Tit)
Molecular weightTheoretical: 127.217016 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPGSGSGMRH RRNGNFESSR LLYSSMSRSI DVACSDADLA NFIQENFKKR ECVFFTKDTK SMGNLCKCGY PENQHIEGTQ VNTTEKWNY KKHTKELPTD AFGDIQFENL GKRGKYIRLS CDTDSETLYD LMTQHWHLKT PNLVISVTGG AKNFALKPRM R KIFSRLIY ...String:
GPGSGSGMRH RRNGNFESSR LLYSSMSRSI DVACSDADLA NFIQENFKKR ECVFFTKDTK SMGNLCKCGY PENQHIEGTQ VNTTEKWNY KKHTKELPTD AFGDIQFENL GKRGKYIRLS CDTDSETLYD LMTQHWHLKT PNLVISVTGG AKNFALKPRM R KIFSRLIY IAQSKGAWIF TGGTHYGLMK YIGEVVRDNT ISRSSEENVV AIGIAAWGMI SNRETLIRTA DSDGSFLARY IM DDLKRDP LYCLDNNHTH LLLVDNGTHG HPTTEAKVRT QLEKYISERV IPESNYGGKI PIVCFAQGGG KETLKSINVA IKS KIPCVV VEGSGRIADV IASLVEAEGT LASSCVKESL LRFLPRTISR LSEEETESWI KWIKEVLESP HLLTVIKIEE AGDE IVSNA ISFALYKAFS TNEHDRDNWN GQLKLLLEWN QLDLASDEIF TNDRNWESAD LQDVMFTALV KDRPKFVRLF LENGL NLRK FLTTEVLREL YTNNFSSLVF KNLQIAKNSY NDALLTFVWK MVEDFRRGFK RDYKNSKDEM EIQLSEECPI TRHPLQ ALF IWSVLQNKKE LSKVIWEQTR GCTLAALGAS KLLKSMAKVK NDINAAGESE ELANEYETRA VELFTECYSN DEDLAEQ LL TYSCEAWGGS NCLELAVEAR DQQFIAQPGV QNFLSKQWYG EISRDTKNWK IIMCLFFFPL IGCGFISFRK KPVEKSKK L FLYYVSFFTS PFVVFSWNVI FYIAFLLLFA YVLLMDFQKE PTALEIILYV LVFVLLCDEV RQWYMNGSKY FSDLWNVMD TLAIFYFIAG IVFRLHSDES SWYSGRVIFC LDYIVFTLRL IHIFTVSRNL GPKIIMLQRM MIDVFFFLFL FAVWMVAFGV ARQGILRKN EHRWEWIFRS VIYEPYLAMF GQYPDDIDGT TYNFDRCTFS GNESKPLCVE LDANNQPRFP EWITIPLVCI Y MLSTNILL VNLLVAMFGY TVGSVQENND QVWKFQRFFL VQEYCSRLTI PFPFVIFAYI FMVMRKCFKC CCNKESKEPS IC CSRNEDN EILAWEAVMK ENYLVKINTK ANDSSEEMVH RFRQLDAKLS DLKGLLKEIS SKIK

UniProtKB: Transient receptor potential cation channel subfamily M member 8

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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 / Material: GOLD / Support film - Material: CARBON / Support film - topology: CONTINUOUS
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 4 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: 1 / Number real images: 35382 / 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

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Details: Initial model determined from a screening dataset and used as an initial reference.
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5) / Number images used: 29248
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5)

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