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- EMDB-42997: Open-state cryo-EM structure of human TRPV3 in presence of 2-APB ... -

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Basic information

Entry
Database: EMDB / ID: EMD-42997
TitleOpen-state cryo-EM structure of human TRPV3 in presence of 2-APB in cNW30 nanodiscs
Map data
Sample
  • Complex: full-length human TRPV3 in complex with 2-APB
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 3
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: ARACHIDONIC ACID
  • Ligand: 2-aminoethyl diphenylborinate
  • Ligand: SODIUM ION
  • Ligand: water
Keywordstransient receptor potential V family member 3 / TRP / channel / TRPV3 / TRP channels / membrane protein / 2-Aminoethoxydiphenylborane / 2-APB
Function / homology
Function and homology information


negative regulation of hair cycle / osmosensory signaling pathway / response to temperature stimulus / TRP channels / positive regulation of calcium ion import / sodium channel activity / calcium ion import across plasma membrane / actin filament organization / calcium ion transmembrane transport / calcium channel activity ...negative regulation of hair cycle / osmosensory signaling pathway / response to temperature stimulus / TRP channels / positive regulation of calcium ion import / sodium channel activity / calcium ion import across plasma membrane / actin filament organization / calcium ion transmembrane transport / calcium channel activity / lysosome / receptor complex / cilium / metal ion binding / identical protein binding / 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 speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsNadezhdin KD / Neuberger A / 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: Sci Adv / Year: 2024
Title: TRPV3 activation by different agonists accompanied by lipid dissociation from the vanilloid site.
Authors: Kirill D Nadezhdin / Arthur Neuberger / Lena S Khosrof / Irina A Talyzina / Jeffrey Khau / Maria V Yelshanskaya / Alexander I Sobolevsky /
Abstract: TRPV3 represents both temperature- and ligand-activated transient receptor potential (TRP) channel. Physiologically relevant opening of TRPV3 channels by heat has been captured structurally, while ...TRPV3 represents both temperature- and ligand-activated transient receptor potential (TRP) channel. Physiologically relevant opening of TRPV3 channels by heat has been captured structurally, while opening by agonists has only been observed in structures of mutant channels. Here, we present cryo-EM structures that illuminate opening and inactivation of wild-type human TRPV3 in response to binding of two types of agonists: either the natural cannabinoid tetrahydrocannabivarin (THCV) or synthetic agonist 2-aminoethoxydiphenylborane (2-APB). We found that THCV binds to the vanilloid site, while 2-APB binds to the S1-S4 base and ARD-TMD linker sites. Despite binding to distally located sites, both agonists induce similar pore opening and cause dissociation of a lipid that occupies the vanilloid site in their absence. Our results uncover different but converging allosteric pathways through which small-molecule agonists activate TRPV3 and provide a framework for drug design and understanding the role of lipids in ion channel function.
History
DepositionDec 1, 2023-
Header (metadata) releaseApr 17, 2024-
Map releaseApr 17, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42997.png

Downloads & links

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Map

FileDownload / File: emd_42997.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.)
0.8 Å/pix.
x 256 pix.
= 204.8 Å		0.8 Å/pix.
x 256 pix.
= 204.8 Å		0.8 Å/pix.
x 256 pix.
= 204.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.241
Minimum - Maximum-1.2372447 - 1.8247392
Average (Standard dev.)0.0026360897 (±0.07380593)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 204.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_42997_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_42997_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : full-length human TRPV3 in complex with 2-APB

EntireName: full-length human TRPV3 in complex with 2-APB
Components
  • Complex: full-length human TRPV3 in complex with 2-APB
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 3
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: ARACHIDONIC ACID
  • Ligand: 2-aminoethyl diphenylborinate
  • Ligand: SODIUM ION
  • Ligand: water

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Supramolecule #1: full-length human TRPV3 in complex with 2-APB

SupramoleculeName: full-length human TRPV3 in complex with 2-APB / 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 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: Homo sapiens (human)
Molecular weightTheoretical: 92.680016 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKAHPKEMVP LMGKRVAAPS GNPAILPEKR PAEITPTKKS AHFFLEIEGF EPNPTVAKTS PPVFSKPMDS NIRQCISGNC DDMDSPQSP QDDVTETPSN PNSPSAQLAK EEQRRKKRRL KKRIFAAVSE GCVEELVELL VELQELCRRR HDEDVPDFLM H KLTASDTG ...String:
MKAHPKEMVP LMGKRVAAPS GNPAILPEKR PAEITPTKKS AHFFLEIEGF EPNPTVAKTS PPVFSKPMDS NIRQCISGNC DDMDSPQSP QDDVTETPSN PNSPSAQLAK EEQRRKKRRL KKRIFAAVSE GCVEELVELL VELQELCRRR HDEDVPDFLM H KLTASDTG KTCLMKALLN INPNTKEIVR ILLAFAEEND ILGRFINAEY TEEAYEGQTA LNIAIERRQG DIAALLIAAG AD VNAHAKG AFFNPKYQHE GFYFGETPLA LAACTNQPEI VQLLMEHEQT DITSRDSRGN NILHALVTVA EDFKTQNDFV KRM YDMILL RSGNWELETT RNNDGLTPLQ LAAKMGKAEI LKYILSREIK EKRLRSLSRK FTDWAYGPVS SSLYDLTNVD TTTD NSVLE ITVYNTNIDN RHEMLTLEPL HTLLHMKWKK FAKHMFFLSF CFYFFYNITL TLVSYYRPRE EEAIPHPLAL THKMG WLQL LGRMFVLIWA MCISVKEGIA IFLLRPSDLQ SILSDAWFHF VFFIQAVLVI LSVFLYLFAY KEYLACLVLA MALGWA NML YYTRGFQSMG MYSVMIQKVI LHDVLKFLFV YIVFLLGFGV ALASLIEKCP KDNKDCSSYG SFSDAVLELF KLTIGLG DL NIQQNSKYPI LFLFLLITYV ILTFVLLLNM LIALMGETVE NVSKESERIW RLQRARTILE FEKMLPEWLR SRFRMGEL C KVAEDDFRLC LRINEVKWTE WKTHVSFLNE DPGPVRRTAD FNKIQDSSRN NSKTTLNAFE EVEEFPETSV LVPRGSAAA WSHPQFEK

UniProtKB: Transient receptor potential cation channel subfamily V member 3

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Macromolecule #2: (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: 2 / Number of copies: 20 / 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 #3: ARACHIDONIC ACID

MacromoleculeName: ARACHIDONIC ACID / type: ligand / ID: 3 / Number of copies: 4 / Formula: ACD
Molecular weightTheoretical: 304.467 Da
Chemical component information

ChemComp-ACD:
ARACHIDONIC ACID

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Macromolecule #4: 2-aminoethyl diphenylborinate

MacromoleculeName: 2-aminoethyl diphenylborinate / type: ligand / ID: 4 / Number of copies: 8 / Formula: FZ4
Molecular weightTheoretical: 225.094 Da
Chemical component information

ChemComp-FZ4:
2-aminoethyl diphenylborinate

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Macromolecule #5: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 5 / Number of copies: 1
Molecular weightTheoretical: 22.99 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 184 / 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

Concentration2 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMtris(hydroxymethyl)aminomethane
1.0 mMbeta-Mercaptoethanol
1.0 mM2-Aminoethoxydiphenylborane
GridModel: UltrAuFoil R1.2/1.3 / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV
Detailshuman TRPV3 in cNW30 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: 2 / Number real images: 25638 / Average exposure time: 1.877 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: 1.5 µm / Nominal defocus min: 0.75 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 12806132
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 105954
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-8v6n:
Open-state cryo-EM structure of human TRPV3 in presence of 2-APB in cNW30 nanodiscs

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