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- EMDB-71303: Cryo-EM structure of full-length human TRPV1 in the presence of a... -

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Entry
Database: EMDB / ID: EMD-71303
TitleCryo-EM structure of full-length human TRPV1 in the presence of alpha-humulene
Map dataCryo-EM structure of full-length human TRPV1 in the presence of alpha-humulene
Sample
  • Complex: full-length human TRPV1 in the presence of alpha-humulene
    • 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: TRIDECANE
  • Ligand: SODIUM ION
  • Ligand: water
Keywordstransient receptor potential V family member 1 / TRP / channel / TRPV1 / TRP channels / sesquiterpene / alpha-humulene / pain / analgesia / MEMBRANE PROTEIN
Function / homology
Function and homology information


chemosensory behavior / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / excitatory extracellular ligand-gated monoatomic ion channel activity / temperature-gated ion channel activity / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition / fever generation / detection of temperature stimulus involved in thermoception ...chemosensory behavior / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / excitatory extracellular ligand-gated monoatomic ion channel activity / temperature-gated ion channel activity / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition / fever generation / detection of temperature stimulus involved in thermoception / thermoception / cellular response to acidic pH / dendritic spine membrane / cellular response to ATP / TRP channels / cellular response to alkaloid / diet induced thermogenesis / detection of temperature stimulus involved in sensory perception of pain / intracellularly gated calcium channel activity / behavioral response to pain / calcium ion import across plasma membrane / voltage-gated calcium channel activity / extracellular ligand-gated monoatomic ion channel activity / phosphatidylinositol binding / phosphoprotein binding / calcium ion transmembrane transport / GABA-ergic synapse / calcium channel activity / lipid metabolic process / transmembrane signaling receptor activity / sensory perception of taste / cellular response to heat / protein homotetramerization / postsynaptic membrane / cell surface receptor signaling pathway / calmodulin binding / negative regulation of transcription by RNA polymerase II / ATP binding / metal ion 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: 2.74 Å
AuthorsTalyzina IA / Sobolevsky AI
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA206573 United States
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R01 AR078814 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 Neurological Disorders and Stroke (NIH/NINDS)R37 NS083660 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Structural basis of the inhibition of TRPV1 by analgesic sesquiterpenes.
Authors: Raúl Sánchez-Hernández / Miguel Benítez-Angeles / Irina A Talyzina / Itzel Llorente / Mariela González-Avendaño / Félix Sierra / Angélica Méndez-Reséndiz / Francisco Mercado / ...Authors: Raúl Sánchez-Hernández / Miguel Benítez-Angeles / Irina A Talyzina / Itzel Llorente / Mariela González-Avendaño / Félix Sierra / Angélica Méndez-Reséndiz / Francisco Mercado / Ariela Vergara-Jaque / Alexander I Sobolevsky / León D Islas / Tamara Rosenbaum /
Abstract: The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in primary nociceptive afferents, which participate in processes such as pain and inflammation. Considerable efforts have ...The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in primary nociceptive afferents, which participate in processes such as pain and inflammation. Considerable efforts have been directed toward finding inhibitors of TRPV1 and understanding the molecular details of their interactions with this channel. α-humulene (AH) is a sesquiterpene derived from plants such as hops and other members of Cannabaceae family, with a long history of popular use as an analgesic and anti-inflammatory. Using a combination of behavioral assays, electrophysiology, site-directed mutagenesis, cryo-EM, and molecular dynamics simulations, we show that AH inhibits TRPV1-related pain responses and currents by interacting with a region composed of the S2, S2-S3 linker, and S3 transmembrane segments and stabilizing the closed conformation of the channel. The interaction of ligands in this region of the TRPV1 channel has not been previously described and the results of the present study highlight that it may constitute part of a negative regulatory region. These findings allow us to understand the molecular basis by which substances such as some sesquiterpenes, abundantly found in medicinal plants used by humans for hundreds of years, reduce pain. Pain management can include the use of opioids, which results in hepatic and renal damage and possible addiction. Our study offers insight into a poorly understood group of compounds that could be used as scaffold to produce novel nonopioid analgesic therapies and clarifies the molecular mechanisms that underlie the effects of these analgesic molecules.
History
DepositionJun 18, 2025-
Header (metadata) releaseJul 23, 2025-
Map releaseJul 23, 2025-
UpdateJul 30, 2025-
Current statusJul 30, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71303.png

Downloads & links

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Map

FileDownload / File: emd_71303.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of full-length human TRPV1 in the presence of alpha-humulene
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.64 Å/pix.
x 320 pix.
= 203.2 Å		0.64 Å/pix.
x 320 pix.
= 203.2 Å		0.64 Å/pix.
x 320 pix.
= 203.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.635 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.02
Minimum - Maximum-0.16134618 - 0.21466908
Average (Standard dev.)0.00048729105 (±0.006432418)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 203.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_71303_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_71303_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : full-length human TRPV1 in the presence of alpha-humulene

EntireName: full-length human TRPV1 in the presence of alpha-humulene
Components
  • Complex: full-length human TRPV1 in the presence of alpha-humulene
    • 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: TRIDECANE
  • Ligand: SODIUM ION
  • Ligand: water

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Supramolecule #1: full-length human TRPV1 in the presence of alpha-humulene

SupramoleculeName: full-length human TRPV1 in the presence of alpha-humulene
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 500 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: 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 #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: TRIDECANE

MacromoleculeName: TRIDECANE / type: ligand / ID: 4 / Number of copies: 4 / Formula: TRD
Molecular weightTheoretical: 184.361 Da
Chemical component information

ChemComp-TRD:
TRIDECANE

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Macromolecule #5: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 5 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / 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

Concentration2.4 mg/mL
BufferpH: 7
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
50.0 mMHEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)
1.0 mMbMEbeta-Mercaptoethanol
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV
Detailshuman TRPV1

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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: 9208 / Average exposure time: 1.318 sec. / Average electron dose: 50.0 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: 2.2 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1693063
CTF correctionSoftware - Name: cryoSPARC (ver. v4.4) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v4.4) / Number images used: 226949
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v4.4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v4.4)
Final 3D classificationNumber classes: 5 / Software - Name: cryoSPARC (ver. v4.4)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-9p6b:
Cryo-EM structure of full-length human TRPV1 in the presence of alpha-humulene

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