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- EMDB-29982: Cryo-EM structure of human TRPV1 in cNW11 nanodisc with POPC:POPE:POPG -

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Basic information

Entry
Database: EMDB / ID: EMD-29982
TitleCryo-EM structure of human TRPV1 in cNW11 nanodisc with POPC:POPE:POPG
Map data
Sample
  • Complex: sample 1
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 1
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctadecanoate
  • Ligand: SODIUM ION
  • Ligand: water
Keywordstransient receptor potential V family member 1 / TRP / apo / human / channel / TRPV1 / TRP channels / pain / membrane protein / cNW11 / nanodiscs / thermo-TRP / temperature sensation / vanilloid / POPC:POPE:POPG
Function / homology
Function and homology information


chemosensory behavior / response to capsazepine / negative regulation of establishment of blood-brain barrier / sensory perception of mechanical stimulus / peptide secretion / excitatory extracellular ligand-gated monoatomic ion channel activity / temperature-gated ion channel activity / cellular response to temperature stimulus / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition ...chemosensory behavior / response to capsazepine / negative regulation of establishment of blood-brain barrier / sensory perception of mechanical stimulus / peptide secretion / excitatory extracellular ligand-gated monoatomic ion channel activity / temperature-gated ion channel activity / cellular response to temperature stimulus / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition / fever generation / thermoception / detection of temperature stimulus involved in thermoception / cellular response to acidic pH / negative regulation of systemic arterial blood pressure / dendritic spine membrane / chloride channel regulator activity / glutamate secretion / TRP channels / negative regulation of heart rate / cellular response to ATP / cellular response to alkaloid / diet induced thermogenesis / intracellularly gated calcium channel activity / behavioral response to pain / detection of temperature stimulus involved in sensory perception of pain / negative regulation of mitochondrial membrane potential / calcium ion import across plasma membrane / voltage-gated calcium channel activity / extracellular ligand-gated monoatomic ion channel activity / phosphatidylinositol binding / GABA-ergic synapse / phosphoprotein binding / microglial cell activation / cellular response to nerve growth factor stimulus / calcium ion transmembrane transport / calcium channel activity / lipid metabolic process / response to peptide hormone / positive regulation of nitric oxide biosynthetic process / transmembrane signaling receptor activity / sensory perception of taste / cellular response to tumor necrosis factor / cellular response to heat / positive regulation of cytosolic calcium ion concentration / protein homotetramerization / postsynaptic membrane / cell surface receptor signaling pathway / calmodulin binding / positive regulation of apoptotic process / external side of plasma membrane / neuronal cell body / negative regulation of transcription by RNA polymerase II / ATP binding / metal ion binding / identical protein binding / membrane / plasma membrane
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 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.58 Å
AuthorsNeuberger A / Nadezhdin KD / Sobolevsky AI
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 Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R01 AR078814 United States
German Research Foundation (DFG)464295817 Germany
CitationJournal: Nat Commun / Year: 2023
Title: Human TRPV1 structure and inhibition by the analgesic SB-366791.
Authors: Arthur Neuberger / Mai Oda / Yury A Nikolaev / Kirill D Nadezhdin / Elena O Gracheva / Sviatoslav N Bagriantsev / Alexander I Sobolevsky /
Abstract: Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller- ...Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller-based treatment is targeting receptors at the origin of the pain pathway, such as transient receptor potential (TRP) ion channels. Thus, a founding member of the vanilloid subfamily of TRP channels, TRPV1, represents one of the most sought-after pain therapy targets. The need for selective TRPV1 inhibitors extends beyond pain treatment, to other diseases associated with this channel, including psychiatric disorders. Here we report the cryo-electron microscopy structures of human TRPV1 in the apo state and in complex with the TRPV1-specific nanomolar-affinity analgesic antagonist SB-366791. SB-366791 binds to the vanilloid site and acts as an allosteric hTRPV1 inhibitor. SB-366791 binding site is supported by mutagenesis combined with electrophysiological recordings and can be further explored to design new drugs targeting TRPV1 in disease conditions.
History
DepositionMar 7, 2023-
Header (metadata) releaseMay 10, 2023-
Map releaseMay 10, 2023-
UpdateOct 9, 2024-
Current statusOct 9, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29982.png

Downloads & links

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Map

FileDownload / File: emd_29982.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.)
0.79 Å/pix.
x 256 pix.
= 200.96 Å		0.79 Å/pix.
x 256 pix.
= 200.96 Å		0.79 Å/pix.
x 256 pix.
= 200.96 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.785 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.156
Minimum - Maximum-0.7381536 - 1.2953777
Average (Standard dev.)0.008092893 (±0.044855904)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 200.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_29982_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_29982_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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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 1
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctadecanoate
  • Ligand: SODIUM ION
  • Ligand: water

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Supramolecule #1: sample 1

SupramoleculeName: sample 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 94.97 KDa

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

MacromoleculeName: Transient receptor potential cation channel subfamily V member 1
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 124.575281 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MTSKKWSSTD LGAAADPLQK DTCPDPLDGD PNSRPPPAKP QLSTAKSRTR LFGKGDSEEA FPVDCPHEEG ELDSCPTITV SPVITIQRP GDGPTGARLL SQDSVAASTE KTLRLYDRRS IFEAVAQNNC QDLESLLLFL QKSKKHLTDN EFKDPETGKT C LLKAMLNL ...String:
MTSKKWSSTD LGAAADPLQK DTCPDPLDGD PNSRPPPAKP QLSTAKSRTR LFGKGDSEEA FPVDCPHEEG ELDSCPTITV SPVITIQRP GDGPTGARLL SQDSVAASTE KTLRLYDRRS IFEAVAQNNC QDLESLLLFL QKSKKHLTDN EFKDPETGKT C LLKAMLNL HDGQNTTIPL LLEIARQTDS LKELVNASYT DSYYKGQTAL HIAIERRNMA LVTLLVENGA DVQAAAHGDF FK KTKGRPG FYFGELPLSL AACTNQLGIV KFLLQNSWQT ADISARDSVG NTVLHALVEV ADNTADNTKF VTSMYNEILM LGA KLHPTL KLEELTNKKG MTPLALAAGT GKIGVLAYIL QREIQEPECR HLSRKFTEWA YGPVHSSLYD LSCIDTCEKN SVLE VIAYS SSETPNRHDM LLVEPLNRLL QDKWDRFVKR IFYFNFLVYC LYMIIFTMAA YYRPVDGLPP FKMEKTGDYF RVTGE ILSV LGGVYFFFRG IQYFLQRRPS MKTLFVDSYS EMLFFLQSLF MLATVVLYFS HLKEYVASMV FSLALGWTNM LYYTRG FQQ MGIYAVMIEK MILRDLCRFM FVYIVFLFGF STAVVTLIED GKNDSLPSES TSHRWRGPAC RPPDSSYNSL YSTCLEL FK FTIGMGDLEF TENYDFKAVF IILLLAYVIL TYILLLNMLI ALMGETVNKI AQESKNIWKL QRAITILDTE KSFLKCMR K AFRSGKLLQV GYTPDGKDDY RWCFRVDEVN WTTWNTNVGI INEDPGNCEG VKRTLSFSLR SSRVSGRHWK NFALVPLLR EASARDRQSA QPEEVYLRQF SGSLKPEDAE VFKSPAASGE KLVPRGSAAA AVSKGEELFT GVVPILVELD GDVNGHKFSV SGEGEGDAT YGKLTLKFIC TTGKLPVPWP TLVTTLTYGV QCFSRYPDHM KQHDFFKSAM PEGYVQERTI FFKDDGNYKT R AEVKFEGD TLVNRIELKG IDFKEDGNIL GHKLEYNYNS HNVYIMADKQ KNGIKVNFKI RHNIEDGSVQ LADHYQQNTP IG DGPVLLP DNHYLSTQSK LSKDPNEKRD HMVLLEFVTA AGITLGMDEL YKSGLRSWSH PQFEK

UniProtKB: Transient receptor potential cation channel subfamily V member 1

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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: 36 / 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: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxyc...

MacromoleculeName: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctadecanoate
type: ligand / ID: 3 / Number of copies: 4 / Formula: 8IJ
Molecular weightTheoretical: 867.138 Da
Chemical component information

ChemComp-8IJ:
(2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctadecanoate

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Macromolecule #4: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 4 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 92 / 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

Concentration2.5 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 / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
Detailshuman TRPV1 reconstituted in cNW11 lipid nanodisc (POPC:POPE:POPG)

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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: 16062 / Average exposure time: 2.0 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: 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: 6558023
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.58 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 778428
Initial angle assignmentType: OTHER / Software - Name: cryoSPARC
Final angle assignmentType: OTHER / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC

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Atomic model buiding 1

SoftwareName: Coot (ver. 0.9.8.1)
RefinementSpace: REAL
Output model

PDB-8gf9:
Cryo-EM structure of human TRPV1 in cNW11 nanodisc and POPC:POPE:POPG lipids

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