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- EMDB-27889: Mouse TRPM8 structure determined in the ligand- and PI(4,5)P2-fre... -

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Basic information

Entry
Database: EMDB / ID: EMD-27889
TitleMouse TRPM8 structure determined in the ligand- and PI(4,5)P2-free condition, Class II, C1 state with endogenous PI(4,5)P2 bound
Map dataFull map, sharpened with B-factor B-50
Sample
  • Complex: Transient receptor potential cation channel subfamily M member 8
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 8
KeywordsTRPM8 / menthol receptor / cold receptor / cold sensor / PI(4 / 5)P2 / cooling agonists / temperature sensing / ion channel / sensory transduction / transient receptor potential ion channel / MEMBRANE PROTEIN
Biological speciesMus musculus (house mouse) / Mus musculus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.13 Å
AuthorsYin Y / Zhang F / Feng S / Butay KJ / Borgnia MJ / Im W / Lee S-Y
Funding support United States, 2 items
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: Science / Year: 2022
Title: Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP.
Authors: Ying Yin / Feng Zhang / Shasha Feng / Kevin John Butay / Mario J Borgnia / Wonpil Im / Seok-Yong Lee /
Abstract: The transient receptor potential melastatin 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is ...The transient receptor potential melastatin 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is controlled by cooling compounds together with the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP). Our knowledge of cold sensation and the therapeutic potential of TRPM8 for neuroinflammatory diseases and pain will be enhanced by understanding the structural basis of cooling agonist- and PIP-dependent TRPM8 activation. We present cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP-dependent gating pathway. Our results uncover two discrete agonist sites, state-dependent rearrangements in the gate positions, and a disordered-to-ordered transition of the gate-forming S6-elucidating the molecular basis of chemically induced cool sensation in mammals.
History
DepositionAug 18, 2022-
Header (metadata) releaseJun 28, 2023-
Map releaseJun 28, 2023-
UpdateJan 10, 2024-
Current statusJan 10, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27889.png

Downloads & links

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Map

FileDownload / File: emd_27889.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map, sharpened with B-factor B-50
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 320 pix.
= 345.6 Å		1.08 Å/pix.
x 320 pix.
= 345.6 Å		1.08 Å/pix.
x 320 pix.
= 345.6 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.7741586 - 1.5553092
Average (Standard dev.)0.0028201586 (±0.042436466)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 345.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27889_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_27889_half_map_1.map
AnnotationHalf map B
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_27889_half_map_2.map
AnnotationHalf map A
Projections & Slices
AxesZYX

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Sample components

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Entire : Transient receptor potential cation channel subfamily M member 8

EntireName: Transient receptor potential cation channel subfamily M member 8
Components
  • Complex: Transient receptor potential cation channel subfamily M member 8
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 8

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

SupramoleculeName: Transient receptor potential cation channel subfamily M member 8
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus
SequenceString: MASFEGARLS MRSRRNGTMG STRTLYSSVS RSTDVSYSDS DLVNFIQANF KKRECVFFTR DSKAMENICK CGYAQSQHIE GTQINQNEKW NYKKHTKEFP TDAFGDIQFE TLGKKGKYLR LSCDTDSETL YELLTQHWHL KTPNLVISVT GGAKNFALKP RMRKIFSRLI ...String:
MASFEGARLS MRSRRNGTMG STRTLYSSVS RSTDVSYSDS DLVNFIQANF KKRECVFFTR DSKAMENICK CGYAQSQHIE GTQINQNEKW NYKKHTKEFP TDAFGDIQFE TLGKKGKYLR LSCDTDSETL YELLTQHWHL KTPNLVISVT GGAKNFALKP RMRKIFSRLI YIAQSKGAWI LTGGTHYGLM KYIGEVVRDN TISRNSEENI VAIGIAAWGM VSNRDTLIRS CDDEGHFSAQ YIMDDFTRDP LYILDNNHTH LLLVDNGCHG HPTVEAKLRN QLEKYISERT SQDSNYGGKI PIVCFAQGGG RETLKAINTS VKSKIPCVVV EGSGQIADVI ASLVEVEDVL TSSMVKEKLV RFLPRTVSRL PEEEIESWIK WLKEILESSH LLTVIKMEEA GDEIVSNAIS YALYKAFSTN EQDKDNWNGQ LKLLLEWNQL DLASDEIFTN DRRWESADLQ EVMFTALIKD RPKFVRLFLE NGLNLQKFLT NEVLTELFST HFSTLVYRNL QIAKNSYNDA LLTFVWKLVA NFRRSFWKED RSSREDLDVE LHDASLTTRH PLQALFIWAI LQNKKELSKV IWEQTKGCTL AALGASKLLK TLAKVKNDIN AAGESEELAN EYETRAVELF TECYSNDEDL AEQLLVYSCE AWGGSNCLEL AVEATDQHFI AQPGVQNFLS KQWYGEISRD TKNWKIILCL FIIPLVGCGL VSFRKKPIDK HKKLLWYYVA FFTSPFVVFS WNVVFYIAFL LLFAYVLLMD FHSVPHTPEL ILYALVFVLF CDEVRQWYMN GVNYFTDLWN VMDTLGLFYF IAGIVFRLHS SNKSSLYSGR VIFCLDYIIF TLRLIHIFTV SRNLGPKIIM LQRMLIDVFF FLFLFAVWMV AFGVARQGIL RQNEQRWRWI FRSVIYEPYL AMFGQVPSDV DSTTYDFSHC TFSGNESKPL CVELDEHNLP RFPEWITIPL VCIYMLSTNI LLVNLLVAMF GYTVGIVQEN NDQVWKFQRY FLVQEYCNRL NIPFPFVVFA YFYMVVKKCF KCCCKEKNME SNACCFRNED NETLAWEGVM KENYLVKINT KANDNSEEMR HRFRQLDSKL NDLKSLLKEI ANNIKSNSLE VLFQGPDYKD DDDKAHHHHH HHHHH

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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
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 2 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 99827 / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 81000
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: 3786942
Startup modelType of model: EMDB MAP
EMDB ID:

7127


Details: The EM map for the previously reported apo TRPM8 structure (EMD-7127) was low-pass filtered to 30-Angstrom and used as an initial model without a reference mask.
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 99827
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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