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- PDB-6wkn: PL-bound rat TRPV2 in nanodiscs -

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Basic information

Entry
Database: PDB / ID: 6wkn
TitlePL-bound rat TRPV2 in nanodiscs
ComponentsTransient receptor potential cation channel subfamily V member 2
KeywordsTRANSPORT PROTEIN / TRP channel / TRPV2 / piperlongumine / ion channel
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 / axonal growth cone / monoatomic cation channel activity / endomembrane system / 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 / axonal growth cone / monoatomic cation channel activity / endomembrane system / calcium channel activity / melanosome / lamellipodium / positive regulation of cold-induced thermogenesis / cell body / axon / negative regulation of cell population proliferation / 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
piperlongumine / Transient receptor potential cation channel subfamily V member 2
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.46 Å
AuthorsPumroy, R.P. / Moiseenkova-Bell, V.Y.
Funding support United States, 2items
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, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 21, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily V member 2
B: Transient receptor potential cation channel subfamily V member 2
C: Transient receptor potential cation channel subfamily V member 2
D: Transient receptor potential cation channel subfamily V member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)348,4658
Polymers347,1964
Non-polymers1,2694
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area22530 Å2
ΔGint-197 kcal/mol
Surface area100400 Å2

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Components

#1: Protein
Transient receptor potential cation channel subfamily V member 2 / TrpV2 / Osm-9-like TRP channel 2 / OTRPC2 / Stretch-activated channel 2B / Vanilloid receptor-like ...TrpV2 / Osm-9-like TRP channel 2 / OTRPC2 / Stretch-activated channel 2B / Vanilloid receptor-like protein 1 / VRL-1


Mass: 86798.891 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Trpv2, Sac2b, Vrl1 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: Q9WUD2
#2: Chemical
ChemComp-LQ4 / piperlongumine / 1-[(2E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoyl]-5,6-dihydropyridin-2(1H)-one


Mass: 317.336 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H19NO5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Homotetramer of full-length rat TRPV2 bound to piperlongumine
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.35 MDa / Experimental value: YES
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Saccharomyces cerevisiae (brewer's yeast)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85584 / Symmetry type: POINT

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