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- PDB-8gf8: Cryo-EM structure of human TRPV1 in cNW11 nanodisc and soybean lipids -

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Basic information

Entry
Database: PDB / ID: 8gf8
TitleCryo-EM structure of human TRPV1 in cNW11 nanodisc and soybean lipids
ComponentsTransient receptor potential cation channel subfamily V member 1
KeywordsMEMBRANE PROTEIN / transient receptor potential V family member 1 / vanilloid / TRP / apo / human / channel / TRPV1 / TRP channels / pain / cNW11 / nanodiscs / thermo-TRP / temperature sensation
Function / homology
Function and homology information


chemosensory behavior / temperature-gated ion channel activity / response to capsazepine / negative regulation of establishment of blood-brain barrier / sensory perception of mechanical stimulus / peptide secretion / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition / cellular response to temperature stimulus / cellular response to acidic pH ...chemosensory behavior / temperature-gated ion channel activity / response to capsazepine / negative regulation of establishment of blood-brain barrier / sensory perception of mechanical stimulus / peptide secretion / detection of chemical stimulus involved in sensory perception of pain / smooth muscle contraction involved in micturition / cellular response to temperature stimulus / cellular response to acidic pH / fever generation / detection of temperature stimulus involved in thermoception / thermoception / negative regulation of systemic arterial blood pressure / glutamate secretion / chloride channel regulator activity / dendritic spine membrane / TRP channels / excitatory extracellular ligand-gated monoatomic ion channel activity / negative regulation of heart rate / cellular response to ATP / cellular response to alkaloid / calcium ion import across plasma membrane / behavioral response to pain / diet induced thermogenesis / detection of temperature stimulus involved in sensory perception of pain / intracellularly gated calcium channel activity / negative regulation of mitochondrial membrane potential / voltage-gated calcium channel activity / extracellular ligand-gated monoatomic ion channel activity / phosphatidylinositol binding / cellular response to nerve growth factor stimulus / phosphoprotein binding / calcium ion transmembrane transport / microglial cell activation / calcium channel activity / lipid metabolic process / response to peptide hormone / positive regulation of nitric oxide biosynthetic process / transmembrane signaling receptor activity / cellular response to tumor necrosis factor / cellular response to heat / positive regulation of cytosolic calcium ion concentration / postsynaptic membrane / protein homotetramerization / 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 / identical protein binding / membrane / metal ion binding / 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 / Transient receptor potential cation channel subfamily V member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsNeuberger, A. / Nadezhdin, K.D. / Sobolevsky, A.I.
Funding support United States, Germany, 5items
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)529,17846
Polymers498,3014
Non-polymers30,87742
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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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


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 / Plasmid: pEG BacMam / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / Variant (production host): suspension-adapted cells / References: UniProt: Q8NER1
#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.: 36 / 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-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
Has ligand of interestN
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: sample 1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.09497 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: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
220 mMtris(hydroxymethyl)aminomethane1
31 mMbeta-Mercaptoethanol1
SpecimenConc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: human TRPV1 reconstituted in cNW11 lipid nanodisc (soybean lipid extract)
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: 277 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: 2000 nm / Nominal defocus min: 750 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 2.8 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 19303
Image scansWidth: 5760 / Height: 4092

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Processing

EM softwareName: PHENIX / Version: 1.11.1_2575: / Category: model refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 8994098
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 323292 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00546236
ELECTRON MICROSCOPYf_angle_d0.91384076
ELECTRON MICROSCOPYf_dihedral_angle_d12.65818448
ELECTRON MICROSCOPYf_chiral_restr0.0443244
ELECTRON MICROSCOPYf_plane_restr0.0056404

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