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- EMDB-24385: Structure of TRPV3 in complex with osthole -

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Basic information

Entry
Database: EMDB / ID: EMD-24385
TitleStructure of TRPV3 in complex with osthole
Map dataTRPV3 in complex with osthole
Sample
  • Complex: sample 1
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 3
  • Ligand: 7-methoxy-8-(3-methylbut-2-enyl)chromen-2-one
KeywordsTRP channel / V3 / MEMBRANE PROTEIN
Function / homology
Function and homology information


negative regulation of hair cycle / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / sodium channel activity / monoatomic ion channel activity / monoatomic cation channel activity / calcium channel activity / lysosome / receptor complex ...negative regulation of hair cycle / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / sodium channel activity / monoatomic ion channel activity / monoatomic cation channel activity / calcium channel activity / lysosome / receptor complex / metal ion binding / identical protein binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
Transient receptor potential cation channel subfamily V member 1-4 / 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 3
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.64 Å
AuthorsNeuberger A / Nadezhdin KD
Funding support United States, Germany, 5 items
OrganizationGrant numberCountry
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 Science Foundation (NSF, United States)1818086 United States
German Research Foundation (DFG)464295817 Germany
CitationJournal: EMBO Rep / Year: 2021
Title: Structural mechanism of TRPV3 channel inhibition by the plant-derived coumarin osthole.
Authors: Arthur Neuberger / Kirill D Nadezhdin / Eleonora Zakharian / Alexander I Sobolevsky /
Abstract: TRPV3, a representative of the vanilloid subfamily of TRP channels, is predominantly expressed in skin keratinocytes and has been implicated in cutaneous sensation and associated with numerous skin ...TRPV3, a representative of the vanilloid subfamily of TRP channels, is predominantly expressed in skin keratinocytes and has been implicated in cutaneous sensation and associated with numerous skin pathologies and cancers. TRPV3 is inhibited by the natural coumarin derivative osthole, an active ingredient of Cnidium monnieri, which has been used in traditional Chinese medicine for the treatment of a variety of human diseases. However, the structural basis of channel inhibition by osthole has remained elusive. Here we present cryo-EM structures of TRPV3 in complex with osthole, revealing two types of osthole binding sites in the transmembrane region of TRPV3 that coincide with the binding sites of agonist 2-APB. Osthole binding converts the channel pore into a previously unidentified conformation with a widely open selectivity filter and closed intracellular gate. Our structures provide insight into competitive inhibition of TRPV3 by osthole and can serve as a template for the design of osthole chemistry-inspired drugs targeting TRPV3-associated diseases.
History
DepositionJul 2, 2021-
Header (metadata) releaseSep 8, 2021-
Map releaseSep 8, 2021-
UpdateJun 5, 2024-
Current statusJun 5, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.325
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.325
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7ras
  • Surface level: 0.325
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24385.png

Downloads & links

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Map

FileDownload / File: emd_24385.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTRPV3 in complex with osthole
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 288 pix.
= 239.04 Å		0.83 Å/pix.
x 288 pix.
= 239.04 Å		0.83 Å/pix.
x 288 pix.
= 239.04 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: 0.325 / Movie #1: 0.325
Minimum - Maximum-1.070417 - 2.053689
Average (Standard dev.)0.02601777 (±0.08236743)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 239.04 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.830.830.83
M x/y/z288288288
origin x/y/z0.0000.0000.000
length x/y/z239.040239.040239.040
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ360360360
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS288288288
D min/max/mean-1.0702.0540.026

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Supplemental data

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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 3
  • Ligand: 7-methoxy-8-(3-methylbut-2-enyl)chromen-2-one

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Supramolecule #1: sample 1

SupramoleculeName: sample 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Transient receptor potential cation channel subfamily V member 3

MacromoleculeName: Transient receptor potential cation channel subfamily V member 3
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 92.481547 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGAHSKEMAP LMGKRTTAPG GNPVVLTEKR PADLTPTKKS AHFFLEIEGF EPNPTVTKTS PPIFSKPMDS NIRQCLSGNC DDMDSPQSP QDDVTETPSN PNSPSANLAK EEQRQKKKRL KKRIFAAVSE GCVEELRELL QDLQDLCRRR RGLDVPDFLM H KLTASDTG ...String:
MGAHSKEMAP LMGKRTTAPG GNPVVLTEKR PADLTPTKKS AHFFLEIEGF EPNPTVTKTS PPIFSKPMDS NIRQCLSGNC DDMDSPQSP QDDVTETPSN PNSPSANLAK EEQRQKKKRL KKRIFAAVSE GCVEELRELL QDLQDLCRRR RGLDVPDFLM H KLTASDTG KTCLMKALLN INPNTKEIVR ILLAFAEEND ILDRFINAEY TEEAYEGQTA LNIAIERRQG DITAVLIAAG AD VNAHAKG VFFNPKYQHE GFYFGETPLA LAACTNQPEI VQLLMENEQT DITSQDSRGN NILHALVTVA EDFKTQNDFV KRM YDMILL RSGNWELETM RNNDGLTPLQ LAAKMGKAEI LKYILSREIK EKPLRSLSRK FTDWAYGPVS SSLYDLTNVD TTTD NSVLE IIVYNTNIDN RHEMLTLEPL HTLLHTKWKK FAKYMFFLSF CFYFFYNITL TLVSYYRPRE DEDLPHPLAL THKMS WLQL LGRMFVLIWA TCISVKEGIA IFLLRPSDLQ SILSDAWFHF VFFVQAVLVI LSVFLYLFAY KEYLACLVLA MALGWA NML AYTRGFQSMG MYSVMIQKVI LHDVLKFLFV YILFLLGFGV ALASLIEKCS KDKKDCSSYG SFSDAVLELF KLTIGLG DL NIQQNSTYPI LFLFLLITYV ILTFVLLLNM LIALMGETVE NVSKESERIW RLQRARTILE FEKMLPEWLR SRFRMGEL C KVADEDFRLC LRINEVKWTE WKTHVSFLNE DPGPIRRTAD LNKIQDSSRS NSKTTLYAFD ELDEFPETSV LVPRGSAAA WSHPQFEK

UniProtKB: Transient receptor potential cation channel subfamily V member 3

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Macromolecule #2: 7-methoxy-8-(3-methylbut-2-enyl)chromen-2-one

MacromoleculeName: 7-methoxy-8-(3-methylbut-2-enyl)chromen-2-one / type: ligand / ID: 2 / Number of copies: 8 / Formula: A0O
Molecular weightTheoretical: 244.286 Da
Chemical component information

ChemComp-A0O:
7-methoxy-8-(3-methylbut-2-enyl)chromen-2-one

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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

Concentration3 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMtris(hydroxymethyl)aminomethane
0.01 %glyco-diosgenin (GDN)
1.0 mMbeta-Mercaptoethanol
400.0 uMosthole
GridModel: C-flat-1.2/1.3 / Material: GOLD / Mesh: 200 / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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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: 3991 / 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: -2.5 µm / Nominal defocus min: -1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1102239
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.64 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.14) / Number images used: 68101
Initial angle assignmentType: OTHER / Software: (Name: RELION (ver. 3.0), cryoSPARC (ver. 2.14))
Final angle assignmentType: OTHER / Software - Name: cryoSPARC (ver. 2.14)
Final 3D classificationSoftware - Name: RELION (ver. 3.0)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-7ras:
Structure of TRPV3 in complex with osthole

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