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- PDB-9nq9: Magnesium ions-bound closed-state cryo-EM structure of human TRPV... -

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Basic information

Entry
Database: PDB / ID: 9nq9
TitleMagnesium ions-bound closed-state cryo-EM structure of human TRPV6 in cNW11 nanodiscs
ComponentsTransient receptor potential cation channel subfamily V member 6
KeywordsMEMBRANE PROTEIN / Transient Receptor Potential V Family Member 6 / TRP / channel / cNW11 / nanodiscs / human / TRPV6 / 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
Chem-POV / CHOLESTEROL HEMISUCCINATE / Transient receptor potential cation channel subfamily V member 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.97 Å
AuthorsNeuberger, A. / Sobolevsky, A.I.
Funding support Germany, United States, 5items
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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 19, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily V member 6
B: Transient receptor potential cation channel subfamily V member 6
C: Transient receptor potential cation channel subfamily V member 6
D: Transient receptor potential cation channel subfamily V member 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)298,20237
Polymers280,0784
Non-polymers18,12333
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 6 / TrpV6 / CaT-like / CaT-L / Calcium transport protein 1 / CaT1 / Epithelial calcium channel 2 / ECaC2


Mass: 70019.570 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPV6, ECAC2 / Production host: Homo sapiens (human) / References: UniProt: Q9H1D0
#2: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C31H50O4
#3: Chemical
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Mg / 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: sample 1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.08322 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
220 mMtris(hydroxymethyl)aminomethane1
31 mMbeta-Mercaptoethanol1
SpecimenConc.: 2.65 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: human TRPV6 reconstituted in cNW11 nanodiscs in the presence of magnesium
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 2 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5706
Image scansWidth: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1RELION3.1particle selection
2SerialEMimage acquisition
4RELION3.1CTF correction
7Cootmodel fitting
9RELION3.1initial Euler assignment
10RELION3.1final Euler assignment
11RELION3.1classification
12RELION3.13D reconstruction
13PHENIXmodel refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 5057951
3D reconstructionResolution: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 31296 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model buildingPDB-ID: 7S8B

7s8b


Accession code: 7S8B / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0119728
ELECTRON MICROSCOPYf_angle_d1.32226776
ELECTRON MICROSCOPYf_dihedral_angle_d16.74111684
ELECTRON MICROSCOPYf_chiral_restr0.0913052
ELECTRON MICROSCOPYf_plane_restr0.0083296

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