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- PDB-9isg: Structure of rat TRPV1 in complex with PSFL426-S5 -

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Basic information

Entry
Database: PDB / ID: 9isg
TitleStructure of rat TRPV1 in complex with PSFL426-S5
ComponentsTransient receptor potential cation channel subfamily V member 1
KeywordsMEMBRANE PROTEIN / TRPV1 / protein complex
Function / homology
Function and homology information


negative regulation of establishment of blood-brain barrier / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / cellular response to temperature stimulus / excitatory extracellular ligand-gated monoatomic ion channel activity / temperature-gated ion channel activity / detection of chemical stimulus involved in sensory perception of pain / TRP channels / smooth muscle contraction involved in micturition ...negative regulation of establishment of blood-brain barrier / response to capsazepine / sensory perception of mechanical stimulus / peptide secretion / cellular response to temperature stimulus / excitatory extracellular ligand-gated monoatomic ion channel activity / temperature-gated ion channel activity / detection of chemical stimulus involved in sensory perception of pain / TRP channels / smooth muscle contraction involved in micturition / fever generation / urinary bladder smooth muscle contraction / detection of temperature stimulus involved in thermoception / thermoception / cellular response to acidic pH / negative regulation of systemic arterial blood pressure / response to pH / chloride channel regulator activity / dendritic spine membrane / glutamate secretion / monoatomic cation transmembrane transporter activity / negative regulation of heart rate / ligand-gated monoatomic ion channel activity / response to pain / temperature homeostasis / diet induced thermogenesis / cellular response to alkaloid / cellular response to ATP / cellular response to cytokine stimulus / detection of temperature stimulus involved in sensory perception of pain / intracellularly gated calcium channel activity / behavioral response to pain / negative regulation of mitochondrial membrane potential / calcium ion import across plasma membrane / monoatomic cation channel activity / extracellular ligand-gated monoatomic ion channel activity / sensory perception of pain / phosphatidylinositol binding / phosphoprotein binding / microglial cell activation / response to peptide hormone / cellular response to nerve growth factor stimulus / GABA-ergic synapse / calcium ion transmembrane transport / cellular response to growth factor stimulus / calcium channel activity / lipid metabolic process / positive regulation of nitric oxide biosynthetic process / cellular response to tumor necrosis factor / calcium ion transport / transmembrane signaling receptor activity / sensory perception of taste / cellular response to heat / positive regulation of cytosolic calcium ion concentration / response to heat / monoatomic ion transmembrane transport / protein homotetramerization / postsynaptic membrane / calmodulin binding / neuron projection / positive regulation of apoptotic process / external side of plasma membrane / neuronal cell body / dendrite / 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 speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsChen, X. / Yu, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32371289 China
CitationJournal: Nat Chem Biol / Year: 2025
Title: Mechanism of capsaicin entry into buried vanilloid sites in TRPV1.
Authors: Meng-Yang Sun / Yu-Jing Bian / Xiao-Ying Chen / Xue Zhang / Ming Li / Bo-Ying Zhou / Yang Yang / Yi-Zhe Huang / Rui Yang / Yu-Hao Gao / Wen-Wen Cui / Ya-Qi Wang / Si-Jia Zhu / Peng Cao / ...Authors: Meng-Yang Sun / Yu-Jing Bian / Xiao-Ying Chen / Xue Zhang / Ming Li / Bo-Ying Zhou / Yang Yang / Yi-Zhe Huang / Rui Yang / Yu-Hao Gao / Wen-Wen Cui / Ya-Qi Wang / Si-Jia Zhu / Peng Cao / Chang-Zhu Li / Michael X Zhu / Yun-Tao Lei / Fan Yang / Ye Yu /
Abstract: The transient receptor potential vanilloid 1 (TRPV1) receptor is a promising target for nonopioid analgesics, yet hyperthermic side effects have hindered drug development. The prevailing perspective ...The transient receptor potential vanilloid 1 (TRPV1) receptor is a promising target for nonopioid analgesics, yet hyperthermic side effects have hindered drug development. The prevailing perspective maintains that extracellular hydrophobic vanilloid ligands, such as capsaicin, traverse the cell membrane to reach the buried vanilloid site during TRPV1 activation. Here, we present an alternative mechanism based on computational and experimental approaches, which suggests a distinct hydrophobic pathway at the TRPV1-cell membrane interface as the principal route for ligand entry to the vanilloid site, rather than direct membrane penetration. Modifications to residues within this pathway greatly delayed capsaicin entry without directly modulating TRPV1 channel gating. A compound designed to occupy this pathway's entrance exhibited analgesic effects without inducing hyperthermia. Cryo-electron microscopy confirmed binding to TRPV1 and its role in perturbing capsaicin entry. Thus, our findings unveil a unique and targetable route for capsaicin access to the TRPV1 vanilloid site.
History
DepositionJul 17, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 23, 2025Provider: repository / Type: Initial release
Revision 1.0Jul 23, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 23, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 23, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jul 23, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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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)399,2168
Polymers398,5834
Non-polymers6334
Water00
1


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

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Components

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


Mass: 99645.812 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Trpv1, Vr1, Vr1l / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: O35433
#2: Chemical
ChemComp-A1D92 / 4-azanyl-3-sulfanylidene-1,2,4-triazine-5,6-dione


Mass: 158.139 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H2N4O2S
Has ligand of interestY
Has protein modificationY

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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: Structure of rat TRPV1 in complex with PSFL426-S5 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: 1600 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 4.5 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 15808 / Symmetry type: POINT

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