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- EMDB-76261: Spermine-blocked open-state cryo-EM structure of human TRPV6 chan... -

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Basic information

Entry
Database: EMDB / ID: EMD-76261
TitleSpermine-blocked open-state cryo-EM structure of human TRPV6 channel in cNW30 nanodiscs
Map data
Sample
  • Complex: spermine-blocked open-state homotetrameric human TRPV6
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 6
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: SPERMINE
  • Ligand: water
Keywordspolyamine / spermine / cancer / cryo-EM / TRP channels / TRPV6 / oncochannel / channel block / MEMBRANE PROTEIN
Function / homology
Function and homology information


parathyroid hormone secretion / regulation of calcium ion-dependent exocytosis / TRP channels / calcium ion import across plasma membrane / calcium ion homeostasis / calcium channel complex / response to calcium ion / calcium ion transmembrane transport / calcium channel activity / calcium ion transport ...parathyroid hormone secretion / regulation of calcium ion-dependent exocytosis / TRP channels / calcium ion import across plasma membrane / calcium ion homeostasis / calcium channel complex / response to calcium ion / calcium ion transmembrane transport / calcium channel activity / calcium ion transport / calmodulin binding / metal ion binding / identical protein binding / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily V member 6 / Transient receptor potential cation channel subfamily V member 5/6 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Ankyrin repeat profile. / Ankyrin repeats (3 copies) / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily ...Transient receptor potential cation channel subfamily V member 6 / Transient receptor potential cation channel subfamily V member 5/6 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / 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 6
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.48 Å
AuthorsNeuberger A / Sobolevsky AI
Funding support Germany, France, United States, 7 items
OrganizationGrant numberCountry
German Research Foundation (DFG)464295817 Germany
Human Frontier Science Program (HFSP) France
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)AR078814 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS083660 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS107253 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA206573 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL181985 United States
CitationJournal: Nat Commun / Year: 2026
Title: Open-channel block of human TRPV6 by polyamine spermine.
Authors: Arthur Neuberger / Irina I Veretenenko / Alexey Shalygin / Yury A Trofimov / Thomas Gudermann / Vladimir Chubanov / Roman G Efremov / Alexander I Sobolevsky /
Abstract: Polyamines are organic cations that are present at sub-millimolar concentrations in the cytoplasm and extracellular fluids and serve as versatile modulators of TRP channels, fine-tuning their ...Polyamines are organic cations that are present at sub-millimolar concentrations in the cytoplasm and extracellular fluids and serve as versatile modulators of TRP channels, fine-tuning their functions in physiological and pathological contexts, including pain, inflammation and cancer. Despite extensive functional studies, the structural basis by which polyamines regulate TRP channels remains unclear. Here, we combine calcium imaging, electrophysiology, cryo-electron microscopy, mutagenesis and molecular dynamics simulations to study regulation of human TRPV6 by polyamine spermine. Our functional experiments demonstrate voltage-dependent block of TRPV6-mediated currents by spermine. Cryo-electron microscopy reveals that spermine binds in the open pore of TRPV6, extending along the pore axis through the selectivity filter and central cavity. Mutagenesis and molecular dynamics simulations confirm the main binding site of spermine in the selectivity filter and suggest a stepwise molecular mechanism of channel block that includes two more binding sites in the pore transiently occupied by spermine. Our findings enrich the knowledge about TRPV6 regulation by endogenous factors and provide details of the ion channel blocking mechanism that can be explored for inhibition of this channel in disease conditions.
History
DepositionMar 23, 2026-
Header (metadata) releaseJun 10, 2026-
Map releaseJun 10, 2026-
UpdateJun 10, 2026-
Current statusJun 10, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76261.png

Downloads & links

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Map

FileDownload / File: emd_76261.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.79 Å/pix.
x 256 pix.
= 201.728 Å		0.79 Å/pix.
x 256 pix.
= 201.728 Å		0.79 Å/pix.
x 256 pix.
= 201.728 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.788 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.075
Minimum - Maximum-0.20089763 - 0.29640445
Average (Standard dev.)0.0031707627 (±0.019891474)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 201.728 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_76261_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_76261_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : spermine-blocked open-state homotetrameric human TRPV6

EntireName: spermine-blocked open-state homotetrameric human TRPV6
Components
  • Complex: spermine-blocked open-state homotetrameric human TRPV6
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 6
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: SPERMINE
  • Ligand: water

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Supramolecule #1: spermine-blocked open-state homotetrameric human TRPV6

SupramoleculeName: spermine-blocked open-state homotetrameric human TRPV6
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 83.22 KDa

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Macromolecule #1: Transient receptor potential cation channel subfamily V member 6

MacromoleculeName: Transient receptor potential cation channel subfamily V member 6
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.01957 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ESWAQSRDEQ NLLQQKRIWE SPLLLAAKDN DVQALNKLLK YEDCKVHQRG AMGETALHIA ALYDNLEAAM VLMEAAPELV FEPMTSELY EGQTALHIAV VNQNMNLVRA LLARRASVSA RATGTAFRRS PCNLIYFGEH PLSFAACVNS EEIVRLLIEH G ADIRAQDS ...String:
ESWAQSRDEQ NLLQQKRIWE SPLLLAAKDN DVQALNKLLK YEDCKVHQRG AMGETALHIA ALYDNLEAAM VLMEAAPELV FEPMTSELY EGQTALHIAV VNQNMNLVRA LLARRASVSA RATGTAFRRS PCNLIYFGEH PLSFAACVNS EEIVRLLIEH G ADIRAQDS LGNTVLHILI LQPNKTFACQ MYNLLLSYDR HGDHLQPLDL VPNHQGLTPF KLAGVEGNTV MFQHLMQKRK HT QWTYGPL TSTLYDLTEI DSSGDEQSLL ELIITTKKRE ARQILDQTPV KELVSLKWKR YGRPYFCMLG AIYLLYIICF TMC CIYRPL KPRTNNRTSP RDNTLLQQKL LQEAYMTPKD DIRLVGELVT VIGAIIILLV EVPDIFRMGV TRFFGQTILG GPFH VLIIT YAFMVLVTMV MRLISASGEV VPMSFALVLG WCNVMYFARG FQMLGPFTIM IQKMIFGDLM RFCWLMAVVI LGFAS AFYI IFQTEDPEEL GHFYDYPMAL FSTFELFLTI IDGPANYNVD LPFMYSITYA AFAIIATLLM LNLLIAMMGD THWRVA HER DELWRAQIVA TTVMLERKLP RCLWPRSGIC GREYGLGDRW FLRVEDRQD

UniProtKB: Transient receptor potential cation channel subfamily V member 6

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Macromolecule #2: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 2 / Number of copies: 12 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #3: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 3 / Number of copies: 4 / Formula: PCW
Molecular weightTheoretical: 787.121 Da
Chemical component information

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

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Macromolecule #4: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 4 / Number of copies: 12 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

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Macromolecule #5: SPERMINE

MacromoleculeName: SPERMINE / type: ligand / ID: 5 / Number of copies: 1 / Formula: SPM
Molecular weightTheoretical: 202.34 Da
Chemical component information

ChemComp-SPM:
SPERMINE

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 4 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration2.5 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMtris(hydroxymethyl)aminomethane
1.0 mMbeta-Mercaptoethanol
10.0 mMspermine
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
Detailshuman TRPV6 reconstituted in cNW30 nanodiscs in the presence of spermine

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 1 / Number real images: 4487 / Average exposure time: 2.0 sec. / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2191044
CTF correctionSoftware - Name: cryoSPARC (ver. 3.3) / Type: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.48 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3) / Number images used: 14018
Initial angle assignmentType: OTHER / Software - Name: cryoSPARC (ver. 3.3)
Final angle assignmentType: OTHER
Final 3D classificationSoftware - Name: cryoSPARC (ver. 3.3)

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Atomic model buiding 1

Initial modelPDB ID:

7s89


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL
Output model

PDB-12ag:
Spermine-blocked open-state cryo-EM structure of human TRPV6 channel in cNW30 nanodiscs

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