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- EMDB-40583: Rat TRPV2 bound with 2 CBD ligands in nanodiscs -

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Basic information

Entry
Database: EMDB / ID: EMD-40583
TitleRat TRPV2 bound with 2 CBD ligands in nanodiscs
Map data
Sample
  • Cell: Trpv2 with CBD ligand
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 2
  • Ligand: cannabidiol
  • Ligand: SODIUM ION
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: water
KeywordsTransport protein / MEMBRANE PROTEIN
Function / homology
Function and homology information


growth cone membrane / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / endomembrane system / positive regulation of axon extension / axonal growth cone / monoatomic cation channel activity / calcium channel activity / melanosome ...growth cone membrane / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / endomembrane system / positive regulation of axon extension / axonal growth cone / monoatomic cation channel activity / calcium channel activity / melanosome / lamellipodium / positive regulation of cold-induced thermogenesis / cell body / negative regulation of cell population proliferation / axon / cell surface / identical protein binding / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily V member 2
Similarity search - Component
Biological speciesHomo sapiens (human) / Rattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.32 Å
AuthorsTan X / Swartz KJ
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) United States
CitationJournal: Elife / Year: 2023
Title: Cannabidiol sensitizes TRPV2 channels to activation by 2-APB.
Authors: Aaron Gochman / Xiao-Feng Tan / Chanhyung Bae / Helen Chen / Kenton J Swartz / Andres Jara-Oseguera /
Abstract: The cation-permeable TRPV2 channel is important for cardiac and immune cell function. Cannabidiol (CBD), a non-psychoactive cannabinoid of clinical relevance, is one of the few molecules known to ...The cation-permeable TRPV2 channel is important for cardiac and immune cell function. Cannabidiol (CBD), a non-psychoactive cannabinoid of clinical relevance, is one of the few molecules known to activate TRPV2. Using the patch-clamp technique, we discover that CBD can sensitize current responses of the rat TRPV2 channel to the synthetic agonist 2-aminoethoxydiphenyl borate (2-APB) by over two orders of magnitude, without sensitizing channels to activation by moderate (40°C) heat. Using cryo-EM, we uncover a new small-molecule binding site in the pore domain of rTRPV2 in addition to a nearby CBD site that had already been reported. The TRPV1 and TRPV3 channels are also activated by 2-APB and CBD and share multiple conserved features with TRPV2, but we find that strong sensitization by CBD is only observed in TRPV3, while sensitization for TRPV1 is much weaker. Mutations at non-conserved positions between rTRPV2 and rTRPV1 in either the pore domain or the CBD sites failed to confer strong sensitization by CBD in mutant rTRPV1 channels. Together, our results indicate that CBD-dependent sensitization of rTRPV2 channels engages multiple channel regions, and that the difference in sensitization strength between rTRPV2 and rTRPV1 channels does not originate from amino acid sequence differences at the CBD binding site or the pore domain. The remarkably robust effect of CBD on TRPV2 and TRPV3 channels offers a promising new tool to both understand and overcome one of the major roadblocks in the study of these channels - their resilience to activation.
History
DepositionApr 24, 2023-
Header (metadata) releaseMay 31, 2023-
Map releaseMay 31, 2023-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40583.png

Downloads & links

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Map

FileDownload / File: emd_40583.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 300 pix.
= 249. Å		0.83 Å/pix.
x 300 pix.
= 249. Å		0.83 Å/pix.
x 300 pix.
= 249. Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.009
Minimum - Maximum-0.025956895 - 0.050977763
Average (Standard dev.)-0.0000044329668 (±0.002483404)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 249.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40583_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_40583_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Trpv2 with CBD ligand

EntireName: Trpv2 with CBD ligand
Components
  • Cell: Trpv2 with CBD ligand
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 2
  • Ligand: cannabidiol
  • Ligand: SODIUM ION
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: water

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Supramolecule #1: Trpv2 with CBD ligand

SupramoleculeName: Trpv2 with CBD ligand / type: cell / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human) / Strain: tsa201

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Macromolecule #1: Transient receptor potential cation channel subfamily V member 2

MacromoleculeName: Transient receptor potential cation channel subfamily V member 2
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 86.798891 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MTSASSPPAF RLETSDGDEE GNAEVNKGKQ EPPPMESPFQ REDRNSSPQI KVNLNFIKRP PKNTSAPSQQ EPDRFDRDRL FSVVSRGVP EELTGLLEYL RWNSKYLTDS AYTEGSTGKT CLMKAVLNLQ DGVNACIMPL LQIDKDSGNP KLLVNAQCTD E FYQGHSAL ...String:
MTSASSPPAF RLETSDGDEE GNAEVNKGKQ EPPPMESPFQ REDRNSSPQI KVNLNFIKRP PKNTSAPSQQ EPDRFDRDRL FSVVSRGVP EELTGLLEYL RWNSKYLTDS AYTEGSTGKT CLMKAVLNLQ DGVNACIMPL LQIDKDSGNP KLLVNAQCTD E FYQGHSAL HIAIEKRSLQ CVKLLVENGA DVHLRACGRF FQKHQGTCFY FGELPLSLAA CTKQWDVVTY LLENPHQPAS LE ATDSLGN TVLHALVMIA DNSPENSALV IHMYDGLLQM GARLCPTVQL EEISNHQGLT PLKLAAKEGK IEIFRHILQR EFS GPYQPL SRKFTEWCYG PVRVSLYDLS SVDSWEKNSV LEIIAFHCKS PNRHRMVVLE PLNKLLQEKW DRLVSRFFFN FACY LVYMF IFTVVAYHQP SLDQPAIPSS KATFGESMLL LGHILILLGG IYLLLGQLWY FWRRRLFIWI SFMDSYFEIL FLLQA LLTV LSQVLRFMET EWYLPLLVLS LVLGWLNLLY YTRGFQHTGI YSVMIQKVIL RDLLRFLLVY LVFLFGFAVA LVSLSR EAR SPKAPEDNNS TVTEQPTVGQ EEEPAPYRSI LDASLELFKF TIGMGELAFQ EQLRFRGVVL LLLLAYVLLT YVLLLNM LI ALMSETVNHV ADNSWSIWKL QKAISVLEME NGYWWCRRKK HREGRLLKVG TRGDGTPDER WCFRVEEVNW AAWEKTLP T LSEDPSGPGI TGNKKNPTSK PGKNSASEED HLPLQVLQSP

UniProtKB: Transient receptor potential cation channel subfamily V member 2

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Macromolecule #2: cannabidiol

MacromoleculeName: cannabidiol / type: ligand / ID: 2 / Number of copies: 8 / Formula: P0T
Molecular weightTheoretical: 314.462 Da
Chemical component information

ChemComp-P0T:
cannabidiol

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Macromolecule #3: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 3 / Number of copies: 1
Molecular weightTheoretical: 22.99 Da

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Macromolecule #4: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 4 / Number of copies: 4 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 4 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: TUNGSTEN HAIRPIN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6u84

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 43071
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-8sly:
Rat TRPV2 bound with 2 CBD ligands in nanodiscs

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