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- EMDB-0638: Structure of the TRPM8 cold receptor by single particle electron ... -

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Basic information

Entry
Database: EMDB / ID: EMD-0638
TitleStructure of the TRPM8 cold receptor by single particle electron cryo-microscopy, TC-I 2014-bound state
Map dataTRPM8 cold receptor, TC-I 2014-bound state
Sample
  • Complex: Transient receptor potential cation channel subfamily M member 8
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 8
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: UNDECANE
  • Ligand: (1R)-2-{[(S)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-1-[(heptanoyloxy)methyl]ethyl octadecanoate
  • Ligand: 3-{7-(trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1H-benzimidazol-2-yl}-1-oxa-2-azaspiro[4.5]dec-2-ene
  • Ligand: SODIUM ION
KeywordsTRANSPORT PROTEIN / Ion Channel / TRPM8
Biological speciesParus major (Great Tit)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsDiver MM / Cheng Y / Julius D
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)R35NS105038 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)R01GM098672 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)S10OD020054 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)S10OD021741 United States
CitationJournal: Science / Year: 2019
Title: Structural insights into TRPM8 inhibition and desensitization.
Authors: Melinda M Diver / Yifan Cheng / David Julius /
Abstract: The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we ...The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we present cryo-electron microscopy structures of TRPM8 in ligand-free, antagonist-bound, or calcium-bound forms, revealing how robust conformational changes give rise to two nonconducting states, closed and desensitized. We describe a malleable ligand-binding pocket that accommodates drugs of diverse chemical structures, and we delineate the ion permeation pathway, including the contribution of lipids to pore architecture. Furthermore, we show that direct calcium binding mediates stimulus-evoked desensitization, clarifying this important mechanism of sensory adaptation. We observe large rearrangements within the S4-S5 linker that reposition the S1-S4 and pore domains relative to the TRP helix, leading us to propose a distinct model for modulation of TRPM8 and possibly other TRP channels.
History
DepositionMar 7, 2019-
Header (metadata) releaseJul 24, 2019-
Map releaseSep 18, 2019-
UpdateMar 20, 2024-
Current statusMar 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6o72
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0638.png

Downloads & links

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Map

FileDownload / File: emd_0638.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTRPM8 cold receptor, TC-I 2014-bound state
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 320 pix.
= 338.88 Å		1.06 Å/pix.
x 320 pix.
= 338.88 Å		1.06 Å/pix.
x 320 pix.
= 338.88 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.059 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.025 / Movie #1: 0.025
Minimum - Maximum-0.14622167 - 0.22519603
Average (Standard dev.)0.00009078733 (±0.0054648346)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 338.88 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0591.0591.059
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z338.880338.880338.880
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.1460.2250.000

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Supplemental data

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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
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: UNDECANE
  • Ligand: (1R)-2-{[(S)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-1-[(heptanoyloxy)methyl]ethyl octadecanoate
  • Ligand: 3-{7-(trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1H-benzimidazol-2-yl}-1-oxa-2-azaspiro[4.5]dec-2-ene
  • Ligand: SODIUM ION

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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: #1
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: 126.989797 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GAMGSRHRRN GNFESSRLLY SSMSRSIDVA CSDADLANFI QENFKKRECV FFTKDTKSMG NLCKCGYPEN QHIEGTQVNT TEKWNYKKH TKELPTDAFG DIQFENLGKR GKYIRLSCDT DSETLYDLMT QHWHLKTPNL VISVTGGAKN FALKPRMRKI F SRLIYIAQ ...String:
GAMGSRHRRN GNFESSRLLY SSMSRSIDVA CSDADLANFI QENFKKRECV FFTKDTKSMG NLCKCGYPEN QHIEGTQVNT TEKWNYKKH TKELPTDAFG DIQFENLGKR GKYIRLSCDT DSETLYDLMT QHWHLKTPNL VISVTGGAKN FALKPRMRKI F SRLIYIAQ SKGAWIFTGG THYGLMKYIG EVVRDNTISR SSEENVVAIG IAAWGMISNR ETLIRTADSD GSFLARYIMD DL KRDPLYC LDNNHTHLLL VDNGTHGHPT TEAKVRTQLE KYISERVIPE SNYGGKIPIV CFAQGGGKET LKSINVAIKS KIP CVVVEG SGRIADVIAS LVEAEGTLAS SCVKESLLRF LPRTISRLSE EETESWIKWI KEVLESPHLL TVIKIEEAGD EIVS NAISF ALYKAFSTNE HDRDNWNGQL KLLLEWNQLD LASDEIFTND RNWESADLQD VMFTALVKDR PKFVRLFLEN GLNLR KFLT TEVLRELYTN NFSSLVFKNL QIAKNSYNDA LLTFVWKMVE DFRRGFKRDY KNSKDEMEIQ LSEECPITRH PLQALF IWS VLQNKKELSK VIWEQTRGCT LAALGASKLL KSMAKVKNDI NAAGESEELA NEYETRAVEL FTECYSNDED LAEQLLT YS CEAWGGSNCL ELAVEARDQQ FIAQPGVQNF LSKQWYGEIS RDTKNWKIIM CLFFFPLIGC GFISFRKKPV EKSKKLFL Y YVSFFTSPFV VFSWNVIFYI AFLLLFAYVL LMDFQKEPTA LEIILYVLVF VLLCDEVRQW YMNGSKYFSD LWNVMDTLA IFYFIAGIVF RLHSDESSWY SGRVIFCLDY IVFTLRLIHI FTVSRNLGPK IIMLQRMMID VFFFLFLFAV WMVAFGVARQ GILRKNEHR WEWIFRSVIY EPYLAMFGQY PDDIDGTTYN FDRCTFSGNE SKPLCVELDA NNQPRFPEWI TIPLVCIYML S TNILLVNL LVAMFGYTVG SVQENNDQVW KFQRFFLVQE YCSRLTIPFP FVIFAYIFMV MRKCFKCCCN KESKEPSICC SR NEDNEIL AWEAVMKENY LVKINTKAND SSEEMVHRFR QLDAKLSDLK GLLKEISSKI K

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Macromolecule #2: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 2 / Number of copies: 4 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #3: UNDECANE

MacromoleculeName: UNDECANE / type: ligand / ID: 3 / Number of copies: 8 / Formula: UND
Molecular weightTheoretical: 156.308 Da
Chemical component information

ChemComp-UND:
UNDECANE

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Macromolecule #4: (1R)-2-{[(S)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-1-[(heptanoy...

MacromoleculeName: (1R)-2-{[(S)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-1-[(heptanoyloxy)methyl]ethyl octadecanoate
type: ligand / ID: 4 / Number of copies: 4 / Formula: 9PE
Molecular weightTheoretical: 593.773 Da
Chemical component information

ChemComp-9PE:
(1R)-2-{[(S)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-1-[(heptanoyloxy)methyl]ethyl octadecanoate / phospholipid*YM

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Macromolecule #5: 3-{7-(trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1H-benzimida...

MacromoleculeName: 3-{7-(trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1H-benzimidazol-2-yl}-1-oxa-2-azaspiro[4.5]dec-2-ene
type: ligand / ID: 5 / Number of copies: 4 / Formula: T14
Molecular weightTheoretical: 467.407 Da
Chemical component information

ChemComp-T14:
3-{7-(trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1H-benzimidazol-2-yl}-1-oxa-2-azaspiro[4.5]dec-2-ene

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Macromolecule #6: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 6 / Number of copies: 8
Molecular weightTheoretical: 22.99 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: 7.4
GridDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 22500
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 59569
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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