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

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Basic information

Entry
Database: PDB / ID: 9p6b
TitleCryo-EM structure of full-length human TRPV1 in the presence of alpha-humulene
ComponentsTransient receptor potential cation channel subfamily V member 1
KeywordsMEMBRANE PROTEIN / transient receptor potential V family member 1 / TRP / channel / TRPV1 / TRP channels / sesquiterpene / alpha-humulene / pain / analgesia
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 / TRP channels / diet induced thermogenesis / cellular response to alkaloid / cellular response to ATP / 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 / GABA-ergic synapse / calcium ion transmembrane transport / calcium channel activity / lipid metabolic process / transmembrane signaling receptor activity / sensory perception of taste / cellular response to heat / protein homotetramerization / postsynaptic membrane / calmodulin binding / cell surface receptor signaling pathway / 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
Chem-8IJ / Chem-POV / TRIDECANE / Transient receptor potential cation channel subfamily V member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.74 Å
AuthorsTalyzina, I.A. / Sobolevsky, A.I.
Funding support United States, 4items
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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 23, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily V member 1
B: Transient receptor potential cation channel subfamily V member 1
C: Transient receptor potential cation channel subfamily V member 1
D: Transient receptor potential cation channel subfamily V member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)526,87646
Polymers498,3014
Non-polymers28,57442
Water1,65792
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Transient receptor potential cation channel subfamily V member 1 / TrpV1 / Capsaicin receptor / Osm-9-like TRP channel 1 / OTRPC1 / Vanilloid receptor 1


Mass: 124575.281 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPV1, VR1 / Cell line (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: Q8NER1

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Non-polymers , 5 types, 134 molecules

#2: Chemical...
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 32 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#3: Chemical
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


Mass: 867.138 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C45H87O13P
#4: Chemical
ChemComp-TRD / TRIDECANE / LIPID FRAGMENT


Mass: 184.361 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C13H28
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 92 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: full-length human TRPV1 in the presence of alpha-humulene
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.50 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: Human embryonic kidney 293 / Plasmid: pEG BacMam
Buffer solutionpH: 7
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
250 mM(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)HEPES1
31 mMbeta-MercaptoethanolbME1
SpecimenConc.: 2.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: human TRPV1
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 700 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 1.318 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 9208
Image scansWidth: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1cryoSPARCv4.4particle selection
4cryoSPARCv4.4CTF correction
9cryoSPARCv4.4initial Euler assignment
10cryoSPARCv4.4final Euler assignment
11cryoSPARCv4.4classification
12cryoSPARCv4.43D reconstruction
13PHENIX1.11.1_2575model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1693063
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 226949 / Symmetry type: POINT
Atomic model buildingSpace: REAL
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00644136
ELECTRON MICROSCOPYf_angle_d0.94978456
ELECTRON MICROSCOPYf_dihedral_angle_d12.41318664
ELECTRON MICROSCOPYf_chiral_restr0.0523316
ELECTRON MICROSCOPYf_plane_restr0.0046468

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