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- PDB-9mkf: Rat TRPV2 bound to AV2-1 agonist -

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Basic information

Entry
Database: PDB / ID: 9mkf
TitleRat TRPV2 bound to AV2-1 agonist
ComponentsTransient receptor potential cation channel subfamily V member 2
KeywordsMEMBRANE PROTEIN / TRP Channel / TRPV2
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 / negative regulation of cell population proliferation / axon / neuronal cell body / 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 / 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: 2.83 Å
AuthorsRocereta, J.A. / Pumroy, R.A. / Moiseenkova-Bell, V.Y.
Funding support United States, Germany, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM144120 United States
German Research Foundation (DFG)SFB TRR152 number 239283807 Germany
CitationJournal: Br J Pharmacol / Year: 2026
Title: Defining AV2-1 as a novel pharmacological probe to target human and rodent TRPV2.
Authors: Andrea Leipe / Julia A Rocereta / Ruth A Pumroy / Andreas Leffler / Michael Schaefer / Vera Moiseenkova-Bell / Kerstin Hill /
Abstract: BACKGROUND AND PURPOSE: Transient receptor potential vanilloid 2 (TRPV2) is a non-selective cation channel implicated in immune cell functions. However, progress in understanding TRPV2 has been ...BACKGROUND AND PURPOSE: Transient receptor potential vanilloid 2 (TRPV2) is a non-selective cation channel implicated in immune cell functions. However, progress in understanding TRPV2 has been limited by a lack of potent and selective pharmacological tools, particularly those targeting the human variant. We aimed to identify and characterise a novel small-molecule activator of TRPV2.
EXPERIMENTAL APPROACH: We screened a compound library using Ca imaging in HEK293 cells stably expressing mouse TRPV2. The lead compound AV2-1 was validated by concentration-response analyses, ...EXPERIMENTAL APPROACH: We screened a compound library using Ca imaging in HEK293 cells stably expressing mouse TRPV2. The lead compound AV2-1 was validated by concentration-response analyses, microfluorometric Ca assays, and electrophysiological recordings. Structural insights were obtained from cryoEM of TRPV2 in complex with AV2-1, and mutagenesis was performed to confirm binding site residues. The efficacy of AV2-1 was assessed in human peripheral blood-derived macrophages by Ca imaging, whole-cell electrophysiology and TIRF microscopy to detect Ca microdomains.
KEY RESULTS: AV2-1 is a novel TRPV2 activator showing robust efficacy across mouse, rat and human orthologues. Structural analysis reveals that AV2-1 stabilises the channel in its active conformation ...KEY RESULTS: AV2-1 is a novel TRPV2 activator showing robust efficacy across mouse, rat and human orthologues. Structural analysis reveals that AV2-1 stabilises the channel in its active conformation by binding to an established intracellular pocket via TRPV2-specific residues His165 and Cys157, as confirmed by mutagenesis experiments. AV2-1 induces TRPV2-dependent global [Ca] signals, ionic currents and localised subplasmalemmal Ca microdomains in human peripheral blood-derived macrophages.
CONCLUSION AND IMPLICATIONS: AV2-1 represents a novel pharmacological tool for probing TRPV2 function in immune cells, combining improved selectivity and potency with low toxicity. Its ability to ...CONCLUSION AND IMPLICATIONS: AV2-1 represents a novel pharmacological tool for probing TRPV2 function in immune cells, combining improved selectivity and potency with low toxicity. Its ability to activate human TRPV2 and elicit physiologically relevant Ca signals highlights its potential for advancing TRPV2 research and for therapeutic exploration in immune modulation and disease contexts.
History
DepositionDec 17, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Primary map / Data content type: Primary map / Provider: 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)352,76616
Polymers347,1964
Non-polymers5,57112
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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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-PEX / 1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE


Mass: 522.632 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C25H49NO8P
#3: Chemical
ChemComp-A1BMB / 1-[(4S)-1-(furan-2-sulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl]cyclopropane-1-carboxylic acid


Mass: 347.386 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H17NO5S / 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: transient receptor potential vanilloid 2 bound to AV2-1 agonist
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.35 MDa / Experimental value: NO
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 25000 nm / Nominal defocus min: 5000 nm
Image recordingElectron dose: 41 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2PHENIX1.20.1_4487:model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.83 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 50412 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00220468
ELECTRON MICROSCOPYf_angle_d0.51927724
ELECTRON MICROSCOPYf_dihedral_angle_d8.4952856
ELECTRON MICROSCOPYf_chiral_restr0.0373108
ELECTRON MICROSCOPYf_plane_restr0.0053380

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