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- EMDB-7824: Cryo-EM structure of human TRPV6-Y467A in amphipols -

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Basic information

Entry
Database: EMDB / ID: EMD-7824
TitleCryo-EM structure of human TRPV6-Y467A in amphipols
Map dataprimary map
Sample
  • Complex: TRPV6 in amphipols
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 6
KeywordsIon channels / transporter / calcium channel / epithelial calcium channel / 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 / 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 / identical protein binding / metal ion 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: 4.34 Å
AuthorsSingh AK / Saotome K
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)1R01CA206573-01A1 United States
CitationJournal: Nat Commun / Year: 2018
Title: Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB.
Authors: Appu K Singh / Kei Saotome / Luke L McGoldrick / Alexander I Sobolevsky /
Abstract: Transient receptor potential (TRP) channels are involved in various physiological processes, including sensory transduction. The TRP channel TRPV6 mediates calcium uptake in epithelia and its ...Transient receptor potential (TRP) channels are involved in various physiological processes, including sensory transduction. The TRP channel TRPV6 mediates calcium uptake in epithelia and its expression is dramatically increased in numerous types of cancer. TRPV6 inhibitors suppress tumor growth, but the molecular mechanism of inhibition remains unknown. Here, we present crystal and cryo-EM structures of human and rat TRPV6 bound to 2-aminoethoxydiphenyl borate (2-APB), a TRPV6 inhibitor and modulator of numerous TRP channels. 2-APB binds to TRPV6 in a pocket formed by the cytoplasmic half of the S1-S4 transmembrane helix bundle. Comparing human wild-type and high-affinity mutant Y467A structures, we show that 2-APB induces TRPV6 channel closure by modulating protein-lipid interactions. Mutagenesis and functional analyses suggest that the identified 2-APB binding site might be present in other members of vanilloid subfamily TRP channels. Our findings reveal a mechanism of ion channel allosteric modulation that can be exploited for therapeutic design.
History
DepositionApr 25, 2018-
Header (metadata) releaseMay 23, 2018-
Map releaseJul 18, 2018-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6d7s
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7824.png

Downloads & links

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Map

FileDownload / File: emd_7824.map.gz / Format: CCP4 / Size: 32.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationprimary map
Voxel sizeX=Y=Z: 0.98 Å
Density
Contour LevelBy AUTHOR: 0.04 / Movie #1: 0.04
Minimum - Maximum-0.074346565 - 0.14482194
Average (Standard dev.)0.0017164394 (±0.008402446)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions204204204
Spacing204204204
CellA=B=C: 199.92 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.980.980.98
M x/y/z204204204
origin x/y/z0.0000.0000.000
length x/y/z199.920199.920199.920
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS204204204
D min/max/mean-0.0740.1450.002

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Supplemental data

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Sample components

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Entire : TRPV6 in amphipols

EntireName: TRPV6 in amphipols
Components
  • Complex: TRPV6 in amphipols
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 6

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Supramolecule #1: TRPV6 in amphipols

SupramoleculeName: TRPV6 in amphipols / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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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: 85.076859 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGLSLPKEKG LILCLWSKFC RWFQRRESWA QSRDEQNLLQ QKRIWESPLL LAAKDNDVQA LNKLLKYEDC KVHQRGAMGE TALHIAALY DNLEAAMVLM EAAPELVFEP MTSELYEGQT ALHIAVVNQN MNLVRALLAR RASVSARATG TAFRRSPCNL I YFGEHPLS ...String:
MGLSLPKEKG LILCLWSKFC RWFQRRESWA QSRDEQNLLQ QKRIWESPLL LAAKDNDVQA LNKLLKYEDC KVHQRGAMGE TALHIAALY DNLEAAMVLM EAAPELVFEP MTSELYEGQT ALHIAVVNQN MNLVRALLAR RASVSARATG TAFRRSPCNL I YFGEHPLS FAACVNSEEI VRLLIEHGAD IRAQDSLGNT VLHILILQPN KTFACQMYNL LLSYDRHGDH LQPLDLVPNH QG LTPFKLA GVEGNTVMFQ HLMQKRKHTQ WTYGPLTSTL YDLTEIDSSG DEQSLLELII TTKKREARQI LDQTPVKELV SLK WKRYGR PYFCMLGAIY LLYIICFTMC CIYRPLKPRT NNRTSPRDNT LLQQKLLQEA YMTPKDDIRL VGELVTVIGA IIIL LVEVP DIFRMGVTRF FGQTILGGPF HVLIITYAFM VLVTMVMRLI SASGEVVPMS FALVLGWCNV MAFARGFQML GPFTI MIQK MIFGDLMRFC WLMAVVILGF ASAFYIIFQT EDPEELGHFY DYPMALFSTF ELFLTIIDGP ANYNVDLPFM YSITYA AFA IIATLLMLNL LIAMMGDTHW RVAHERDELW RAQIVATTVM LERKLPRCLW PRSGICGREY GLGDRWFLRV EDRQDLN RQ RIQRYAQAFH TRGSEDLDKD SVEKLELGCP FSPHLSLPMP SVSRSTSRSS ANWERLRQGT LRRDLRGIIN RGLEDGES W EYQILVPRGS AAAWSHPQFE K

UniProtKB: Transient receptor potential cation channel subfamily V member 6

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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

Concentration0.5 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClSodium chloridesodium chloride
20.0 mMTRISTRIS
GridMaterial: GOLD / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy

MicroscopeFEI TECNAI F30
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 67.0 e/Å2
Experimental equipment
Model: Tecnai F30 / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

7120

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C4 (4 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 4.34 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 115126

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