+Open data
-Basic information
Entry | Database: PDB / ID: 6wkn | |||||||||
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Title | PL-bound rat TRPV2 in nanodiscs | |||||||||
Components | Transient receptor potential cation channel subfamily V member 2 | |||||||||
Keywords | TRANSPORT 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 / endomembrane system / positive regulation of axon extension / axonal growth cone / monoatomic cation channel activity / calcium channel activity ...growth cone membrane / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / calcium ion import across plasma membrane / endomembrane system / positive regulation of axon extension / axonal growth cone / monoatomic cation channel activity / calcium channel activity / melanosome / lamellipodium / cell body / positive regulation of cold-induced thermogenesis / negative regulation of cell population proliferation / axon / cell surface / identical protein binding / plasma membrane Similarity search - Function | |||||||||
Biological species | Rattus norvegicus (Norway rat) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.46 Å | |||||||||
Authors | Pumroy, R.P. / Moiseenkova-Bell, V.Y. | |||||||||
Funding support | United States, 2items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6wkn.cif.gz | 425.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6wkn.ent.gz | 347.9 KB | Display | PDB format |
PDBx/mmJSON format | 6wkn.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/wk/6wkn ftp://data.pdbj.org/pub/pdb/validation_reports/wk/6wkn | HTTPS FTP |
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-Related structure data
Related structure data | 21705MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | 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 / Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Homotetramer of full-length rat TRPV2 bound to piperlongumine Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Value: 0.35 MDa / Experimental value: YES |
Source (natural) | Organism: Rattus norvegicus (Norway rat) |
Source (recombinant) | Organism: Saccharomyces cerevisiae (brewer's yeast) |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Details: unspecified |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy |
Image recording | Electron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85584 / Symmetry type: POINT |