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- EMDB-21705: PL-bound rat TRPV2 in nanodiscs -

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Basic information

Entry
Database: EMDB / ID: EMD-21705
TitlePL-bound rat TRPV2 in nanodiscs
Map datasharpened map
Sample
  • Complex: Homotetramer of full-length rat TRPV2 bound to piperlongumine
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 2
  • Ligand: piperlongumine
KeywordsTRP channel / TRPV2 / piperlongumine / ion channel / TRANSPORT PROTEIN
Function / homology
Function and homology information


growth cone membrane / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / calcium ion import across plasma membrane / positive regulation of axon extension / endomembrane system / monoatomic cation channel activity / axonal growth cone / calcium channel activity ...growth cone membrane / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / calcium ion import across plasma membrane / positive regulation of axon extension / endomembrane system / monoatomic cation channel activity / axonal growth cone / 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 speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.46 Å
AuthorsPumroy RP / Moiseenkova-Bell VY
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM103899 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM129357 United States
CitationJournal: ACS Cent Sci / Year: 2021
Title: Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression.
Authors: João Conde / Ruth A Pumroy / Charlotte Baker / Tiago Rodrigues / Ana Guerreiro / Bárbara B Sousa / Marta C Marques / Bernardo P de Almeida / Sohyon Lee / Elvira P Leites / Daniel Picard / ...Authors: João Conde / Ruth A Pumroy / Charlotte Baker / Tiago Rodrigues / Ana Guerreiro / Bárbara B Sousa / Marta C Marques / Bernardo P de Almeida / Sohyon Lee / Elvira P Leites / Daniel Picard / Amrita Samanta / Sandra H Vaz / Florian Sieglitz / Maike Langini / Marc Remke / Rafael Roque / Tobias Weiss / Michael Weller / Yuhang Liu / Seungil Han / Francisco Corzana / Vanessa A Morais / Cláudia C Faria / Tânia Carvalho / Panagis Filippakopoulos / Berend Snijder / Nuno L Barbosa-Morais / Vera Y Moiseenkova-Bell / Gonçalo J L Bernardes /
Abstract: The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to ...The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to deconvolute the phenotypic effects of piperlongumine (PL) and establish a link to modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to a transient allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Calcium imaging experiments revealed the importance of Arg539 and Thr522 residues on the antagonistic effect of PL and calcium influx modulation of the TRPV2 channel. Downregulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression, and poor prognosis. Extensive tumor abrogation and long term survival was achieved in two murine models of orthotopic GBM by formulating PL in an implantable scaffold/hydrogel for sustained local therapy. Furthermore, in primary tumor samples derived from GBM patients, we observed a selective reduction of malignant cells in response to PL . Our results establish a broadly applicable strategy, leveraging data-motivated research hypotheses for the discovery of novel means tackling cancer.
History
DepositionApr 16, 2020-
Header (metadata) releaseApr 21, 2021-
Map releaseApr 21, 2021-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6wkn
  • Surface level: 0.018
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21705.png

Downloads & links

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Map

FileDownload / File: emd_21705.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Voxel sizeX=Y=Z: 0.838 Å
Density
Contour LevelBy AUTHOR: 0.016 / Movie #1: 0.018
Minimum - Maximum-0.052686866 - 0.11031803
Average (Standard dev.)0.00043194584 (±0.0038823271)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 214.528 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8380.8380.838
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z214.528214.528214.528
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0530.1100.000

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Supplemental data

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Additional map: unsharpened map

Fileemd_21705_additional_1.map
Annotationunsharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 1

Fileemd_21705_half_map_1.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_21705_half_map_2.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Homotetramer of full-length rat TRPV2 bound to piperlongumine

EntireName: Homotetramer of full-length rat TRPV2 bound to piperlongumine
Components
  • Complex: Homotetramer of full-length rat TRPV2 bound to piperlongumine
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 2
  • Ligand: piperlongumine

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Supramolecule #1: Homotetramer of full-length rat TRPV2 bound to piperlongumine

SupramoleculeName: Homotetramer of full-length rat TRPV2 bound to piperlongumine
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 350 KDa

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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: Saccharomyces cerevisiae (brewer's yeast)
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: piperlongumine

MacromoleculeName: piperlongumine / type: ligand / ID: 2 / Number of copies: 4 / Formula: LQ4
Molecular weightTheoretical: 317.336 Da
Chemical component information

ChemComp-LQ4:
piperlongumine / alkaloid*YM

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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
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: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

20677

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 85584
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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