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- EMDB-49646: Magnesium ions-bound closed-state cryo-EM structure of human TRPV... -

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Basic information

Entry
Database: EMDB / ID: EMD-49646
TitleMagnesium ions-bound closed-state cryo-EM structure of human TRPV6 in cNW11 nanodiscs
Map dataMagnesium ions-bound closed-state cryo-EM structure of human TRPV6 in cNW11 nanodiscs
Sample
  • Complex: sample 1
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 6
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: MAGNESIUM ION
KeywordsTransient Receptor Potential V Family Member 6 / TRP / channel / cNW11 / nanodiscs / human / TRPV6 / membrane protein / magnesium / ions / closed state
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 repeats (3 copies) / Ankyrin repeat profile. / 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 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
Transient receptor potential cation channel subfamily V member 6
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.97 Å
AuthorsNeuberger A / Sobolevsky AI
Funding support Germany, United States, 5 items
OrganizationGrant numberCountry
German Research Foundation (DFG)464295817 Germany
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA206573 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS083660 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS107253 United States
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R01 AR078814 United States
CitationJournal: Nat Commun / Year: 2025
Title: The locking mechanism of human TRPV6 inhibition by intracellular magnesium.
Authors: Arthur Neuberger / Alexey Shalygin / Irina I Veretenenko / Yury A Trofimov / Thomas Gudermann / Vladimir Chubanov / Roman G Efremov / Alexander I Sobolevsky /
Abstract: TRPV6 is a member of the vanilloid subfamily of transient receptor potential channels, which serves as the master regulator of Ca homeostasis. TRPV6 functions as a constitutively active Ca channel, ...TRPV6 is a member of the vanilloid subfamily of transient receptor potential channels, which serves as the master regulator of Ca homeostasis. TRPV6 functions as a constitutively active Ca channel, and emerging evidence indicates that its overactivity underpins the progression of several human diseases, including cancer. Hence, there is a pressing need to identify TRPV6 inhibitors in conjunction with a deep mechanistic understanding of their effects on the channel activity. Here we combine cryo-electron microscopy, mutagenesis, electrophysiology and molecular dynamics modeling to decipher the molecular mechanism of TRPV6 inhibition by intracellular Mg. Mg appears to bind to four, one per subunit, sites around the intracellular entrance to the TRPV6 channel pore, contributed by the negatively charged residues, D489 in the transmembrane helix S5 and D580 in S6. When bound to the D489-D580 site, Mg prevents the α-to-π transition in the middle of S6 that accompanies channel opening, thus maintaining S6 entirely α-helical, locking the channel in the closed state and inhibiting TRPV6-mediated currents. Further exploration of this inhibitory mechanism may help to develop future strategies for the treatment of TRPV6-associated diseases.
History
DepositionMar 12, 2025-
Header (metadata) releaseNov 19, 2025-
Map releaseNov 19, 2025-
UpdateNov 19, 2025-
Current statusNov 19, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49646.png

Downloads & links

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Map

FileDownload / File: emd_49646.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMagnesium ions-bound closed-state cryo-EM structure of human TRPV6 in cNW11 nanodiscs
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.224 Å		0.83 Å/pix.
x 256 pix.
= 212.224 Å		0.83 Å/pix.
x 256 pix.
= 212.224 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.829 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0172
Minimum - Maximum-0.057349365 - 0.12538421
Average (Standard dev.)0.00036868168 (±0.0039997315)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.224 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_49646_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_49646_half_map_2.map
AnnotationHalf 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 : sample 1

EntireName: sample 1
Components
  • Complex: sample 1
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 6
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: MAGNESIUM ION

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Supramolecule #1: sample 1

SupramoleculeName: sample 1 / 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: (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: 3 / Number of copies: 16 / 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 #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 5 / Formula: MG
Molecular weightTheoretical: 24.305 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

Concentration2.65 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMtris(hydroxymethyl)aminomethane
1.0 mMbeta-Mercaptoethanol
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 cNW11 nanodiscs in the presence of magnesium

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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: 5706 / 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: 5057951
CTF correctionSoftware - Name: RELION (ver. 3.1) / Type: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 31296
Initial angle assignmentType: OTHER / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: OTHER / Software - Name: RELION (ver. 3.1)
Final 3D classificationSoftware - Name: RELION (ver. 3.1)

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Atomic model buiding 1

Initial modelPDB ID:

7s8b


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

PDB-9nq9:
Magnesium ions-bound closed-state cryo-EM structure of human TRPV6 in cNW11 nanodiscs

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