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- EMDB-48325: Rat TRPV2 bound to AV2-1 agonist -

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Basic information

Entry
Database: EMDB / ID: EMD-48325
TitleRat TRPV2 bound to AV2-1 agonist
Map dataTRPV2 and AV2-1 agonist
Sample
  • Complex: transient receptor potential vanilloid 2 bound to AV2-1 agonist
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 2
  • Ligand: 1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE
  • Ligand: 1-[(4S)-1-(furan-2-sulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl]cyclopropane-1-carboxylic acid
KeywordsTRP Channel / TRPV2 / MEMBRANE 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 / 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 / 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 repeat profile. / Ankyrin repeats (3 copies) / 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: 2.83 Å
AuthorsRocereta JA / Pumroy RA / Moiseenkova-Bell VY
Funding support United States, Germany, 2 items
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, 2024-
Header (metadata) releaseApr 15, 2026-
Map releaseApr 15, 2026-
UpdateApr 15, 2026-
Current statusApr 15, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48325.png

Downloads & links

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Map

FileDownload / File: emd_48325.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTRPV2 and AV2-1 agonist
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 320 pix.
= 267.52 Å		0.84 Å/pix.
x 320 pix.
= 267.52 Å		0.84 Å/pix.
x 320 pix.
= 267.52 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.836 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.276
Minimum - Maximum-1.2441535 - 2.4067988
Average (Standard dev.)0.0048531997 (±0.05504541)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 267.52002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: TRPV2 and AV2-1 agonist, Half Map A

Fileemd_48325_half_map_1.map
AnnotationTRPV2 and AV2-1 agonist, Half Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: TRPV2 and AV2-1 agonist, Half Map B

Fileemd_48325_half_map_2.map
AnnotationTRPV2 and AV2-1 agonist, Half Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : transient receptor potential vanilloid 2 bound to AV2-1 agonist

EntireName: transient receptor potential vanilloid 2 bound to AV2-1 agonist
Components
  • Complex: transient receptor potential vanilloid 2 bound to AV2-1 agonist
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 2
  • Ligand: 1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE
  • Ligand: 1-[(4S)-1-(furan-2-sulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl]cyclopropane-1-carboxylic acid

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Supramolecule #1: transient receptor potential vanilloid 2 bound to AV2-1 agonist

SupramoleculeName: transient receptor potential vanilloid 2 bound to AV2-1 agonist
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: 1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE

MacromoleculeName: 1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / type: ligand / ID: 2 / Number of copies: 8 / Formula: PEX
Molecular weightTheoretical: 522.632 Da
Chemical component information

ChemComp-PEX:
1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE

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Macromolecule #3: 1-[(4S)-1-(furan-2-sulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl]cycl...

MacromoleculeName: 1-[(4S)-1-(furan-2-sulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl]cyclopropane-1-carboxylic acid
type: ligand / ID: 3 / Number of copies: 4 / Formula: A1BMB
Molecular weightTheoretical: 347.386 Da

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 41.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 25.0 µm / Nominal defocus min: 5.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

20677

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.83 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 50412
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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