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- PDB-9b3y: Rat TRPV2 E724A/D725A bound to probenecid -

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Basic information

Entry
Database: PDB / ID: 9b3y
TitleRat TRPV2 E724A/D725A bound to probenecid
ComponentsTransient receptor potential cation channel subfamily V member 2
KeywordsMEMBRANE PROTEIN / TRPV2 / TRP channel / probenecid / 2-APB
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 / axonal growth cone / positive regulation of axon extension / 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 / axonal growth cone / positive regulation of axon extension / monoatomic cation channel activity / endomembrane system / 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
1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / 4-(dipropylsulfamoyl)benzoic acid / 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: 2.7 Å
AuthorsRocereta, J.A. / Pumroy, R.A. / Moiseenkova-Bell, V.Y.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM144120 United States
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Structural insights into TRPV2 modulation by probenecid.
Authors: Julia A Rocereta / Toni Sturhahn / Ruth A Pumroy / Tabea C Fricke / Christine Herzog / Andreas Leffler / Vera Moiseenkova-Bell /
Abstract: The transient receptor potential vanilloid 2 (TRPV2) cation channel is a key player in cardiovascular physiology and pathophysiology. Probenecid (PBC), an FDA-approved uricosuric agent thought to ...The transient receptor potential vanilloid 2 (TRPV2) cation channel is a key player in cardiovascular physiology and pathophysiology. Probenecid (PBC), an FDA-approved uricosuric agent thought to activate TRPV2, has shown promise in enhancing cardiovascular function in both preclinical and clinical studies. Here our electrophysiological data reveal that PBC significantly potentiates rat TRPV2 to known stimuli, and cryo electron microscopy structures show that PBC directly interacts with rat TRPV2 in a previously unidentified intracellular binding pocket. PBC binding at a conserved TRPV2-specific histidine prevents the channel from taking on the inactivated carboxyl-terminal conformation. This effect extends to TRPV1 and TRPV3 channels when glutamine is substituted with histidine at the corresponding position, increasing their sensitivity to PBC. While PBC alone does not induce TRPV2 opening, its combination with 2-aminoethoxydiphenyl borate enables the channel to adopt an intermediate, potentiated state. Our results offer insights into potential therapeutic advancements for TRPV2 through this pocket.
History
DepositionMar 20, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 26, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)350,01912
Polymers346,7874
Non-polymers3,2328
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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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: 86696.844 Da / Num. of mol.: 4 / Mutation: E724A,D725A
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-PEX / 1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE


Mass: 522.632 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H49NO8P
#3: Chemical
ChemComp-RTO / 4-(dipropylsulfamoyl)benzoic acid


Mass: 285.359 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C13H19NO4S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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 rat TRPV2 E724A/D725A mutant / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
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
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 / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 41.3 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 231568 / Symmetry type: POINT

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