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- EMDB-45935: Structure of human full-length derived TRPV6 channel in apo open state -

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Basic information

Entry
Database: EMDB / ID: EMD-45935
TitleStructure of human full-length derived TRPV6 channel in apo open state
Map data
Sample
  • Complex: derived hTRPV6 tetramer in open apo state
    • 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: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CALCIUM ION
  • Ligand: water
Keywordstransient receptor potential V family member 6 / TRP / channel / TRPV6 / TRP channels / membrane protein / derived
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 / calcium ion transmembrane transport / calcium channel activity / response to calcium ion / 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 / calcium ion transmembrane transport / calcium channel activity / response to calcium ion / 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: 2.78 Å
AuthorsNeuberger A / Nadezhdin KD / Sobolevsky AI
Funding support United States, Germany, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R01 AR078814 United States
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
German Research Foundation (DFG)464295817 Germany
CitationJournal: Structure / Year: 2025
Title: Structure-function analyses of human TRPV6 ancestral and derived haplotypes.
Authors: Arthur Neuberger / Alexey Shalygin / Yury A Trofimov / Irina I Veretenenko / Kirill D Nadezhdin / Nikolay A Krylov / Thomas Gudermann / Roman G Efremov / Vladimir Chubanov / Alexander I Sobolevsky /
Abstract: TRPV6 is a Ca selective channel that mediates calcium uptake in the gut and contributes to the development and progression of human cancers. TRPV6 is represented by the ancestral and derived ...TRPV6 is a Ca selective channel that mediates calcium uptake in the gut and contributes to the development and progression of human cancers. TRPV6 is represented by the ancestral and derived haplotypes that differ by three non-synonymous polymorphisms, located in the N-terminal ankyrin repeat domain (C157R), S1-S2 extracellular loop (M378V), and C-terminus (M681T). The ancestral and derived haplotypes were proposed to serve as genomic factors causing a different outcome for cancer patients of African ancestry. We solved cryoelectron microscopy (cryo-EM) structures of ancestral and derived TRPV6 in the open and calmodulin (CaM)-bound inactivated states. Neither state shows substantial structural differences caused by the non-synonymous polymorphisms. Functional properties assessed by electrophysiological recordings and Ca uptake measurements, and water and ion permeation evaluated by molecular modeling also appear similar between the haplotypes. Therefore, ancestral and derived TRPV6 have similar structure and function, implying that other factors are responsible for the differences in susceptibility to cancer.
History
DepositionJul 26, 2024-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateJan 15, 2025-
Current statusJan 15, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45935.png

Downloads & links

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Map

FileDownload / File: emd_45935.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.)
0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0959
Minimum - Maximum-1.7942929 - 2.508886
Average (Standard dev.)0.0029018032 (±0.07640777)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_45935_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_45935_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : derived hTRPV6 tetramer in open apo state

EntireName: derived hTRPV6 tetramer in open apo state
Components
  • Complex: derived hTRPV6 tetramer in open apo state
    • 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: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CALCIUM ION
  • Ligand: water

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Supramolecule #1: derived hTRPV6 tetramer in open apo state

SupramoleculeName: derived hTRPV6 tetramer in open apo state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 370 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: 87.3835 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGPLQGDGGP ALGGADVAPR LSPVRVWPRP QAPKEPALHP MGLSLPKEKG LILCLWSKFC RWFQRRESWA QSRDEQNLLQ QKRIWESPL LLAAKDNDVQ ALNKLLKYED CKVHQRGAMG ETALHIAALY DNLEAAMVLM EAAPELVFEP MTSELYEGQT A LHIAVVNQ ...String:
MGPLQGDGGP ALGGADVAPR LSPVRVWPRP QAPKEPALHP MGLSLPKEKG LILCLWSKFC RWFQRRESWA QSRDEQNLLQ QKRIWESPL LLAAKDNDVQ ALNKLLKYED CKVHQRGAMG ETALHIAALY DNLEAAMVLM EAAPELVFEP MTSELYEGQT A LHIAVVNQ NMNLVRALLA RRASVSARAT GTAFRRSPCN LIYFGEHPLS FAACVNSEEI VRLLIEHGAD IRAQDSLGNT VL HILILQP NKTFACQMYN LLLSYDRHGD HLQPLDLVPN HQGLTPFKLA GVEGNTVMFQ HLMQKRKHTQ WTYGPLTSTL YDL TEIDSS GDEQSLLELI ITTKKREARQ ILDQTPVKEL VSLKWKRYGR PYFCMLGAIY LLYIICFTMC CIYRPLKPRT NNRT SPRDN TLLQQKLLQE AYMTPKDDIR LVGELVTVIG AIIILLVEVP DIFRMGVTRF FGQTILGGPF HVLIITYAFM VLVTM VMRL ISASGEVVPM SFALVLGWCN VMYFARGFQM LGPFTIMIQK MIFGDLMRFC WLMAVVILGF ASAFYIIFQT EDPEEL GHF YDYPMALFST FELFLTIIDG PANYNVDLPF MYSITYAAFA IIATLLMLNL LIAMMGDTHW RVAHERDELW RAQIVAT TV MLERKLPRCL WPRSGICGRE YGLGDRWFLR VEDRQDLNRQ RIQRYAQAFH TRGSEDLDKD SVEKLELGCP FSPHLSLP M PSVSRSTSRS SANWERLRQG TLRRDLRGII NRGLEDGESW EYQI

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: 32 / 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: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 4 / Number of copies: 20 / 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 #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 72 / 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

Concentration1.9 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 / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV
Detailshuman TRPV6 in cNW11 nanodiscs

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 11520 pixel / Digitization - Dimensions - Height: 8184 pixel / Number grids imaged: 1 / Number real images: 12516 / Average exposure time: 2.5 sec. / Average electron dose: 58.0 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: 9029804
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.78 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 554157
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-9cuj:
Structure of human full-length derived TRPV6 channel in apo open state

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