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Yorodumi- PDB-8gf9: Cryo-EM structure of human TRPV1 in cNW11 nanodisc and POPC:POPE:... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8gf9 | ||||||||||||||||||
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Title | Cryo-EM structure of human TRPV1 in cNW11 nanodisc and POPC:POPE:POPG lipids | ||||||||||||||||||
Components | Transient receptor potential cation channel subfamily V member 1TRPV1 | ||||||||||||||||||
Keywords | MEMBRANE PROTEIN / transient receptor potential V family member 1 / TRP / apo / human / channel / TRPV1 / TRP channels / pain / cNW11 / nanodiscs / thermo-TRP / temperature sensation / vanilloid / POPC:POPE:POPG | ||||||||||||||||||
Function / homology | Function and homology information chemosensory behavior / temperature-gated ion channel activity / response to capsazepine / excitatory extracellular ligand-gated monoatomic ion channel activity / 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 / cellular response to temperature stimulus / smooth muscle contraction involved in micturition ...chemosensory behavior / temperature-gated ion channel activity / response to capsazepine / excitatory extracellular ligand-gated monoatomic ion channel activity / 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 / cellular response to temperature stimulus / smooth muscle contraction involved in micturition / cellular response to acidic pH / thermoception / fever generation / detection of temperature stimulus involved in thermoception / glutamate secretion / dendritic spine membrane / negative regulation of systemic arterial blood pressure / chloride channel regulator activity / TRP channels / cellular response to ATP / negative regulation of heart rate / cellular response to alkaloid / behavioral response to pain / diet induced thermogenesis / extracellular ligand-gated monoatomic ion channel activity / intracellularly gated calcium channel activity / negative regulation of mitochondrial membrane potential / detection of temperature stimulus involved in sensory perception of pain / calcium ion import across plasma membrane / voltage-gated calcium 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 heat / cellular response to tumor necrosis factor / 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 / membrane / identical protein binding / metal ion binding / plasma membrane Similarity search - Function | ||||||||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.58 Å | ||||||||||||||||||
Authors | Neuberger, A. / Nadezhdin, K.D. / Sobolevsky, A.I. | ||||||||||||||||||
Funding support | United States, Germany, 5items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8gf9.cif.gz | 845.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8gf9.ent.gz | 708.9 KB | Display | PDB format |
PDBx/mmJSON format | 8gf9.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/gf/8gf9 ftp://data.pdbj.org/pub/pdb/validation_reports/gf/8gf9 | HTTPS FTP |
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-Related structure data
Related structure data | 29982MC 8gf8C 8gfaC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | 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 / ( #3: Chemical | ChemComp-8IJ / ( #4: Chemical | #5: Water | ChemComp-HOH / | Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: sample 1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT | ||||||||||||||||||||
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Molecular weight | Value: 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 solution | pH: 8 | ||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES Details: human TRPV1 reconstituted in cNW11 lipid nanodisc (POPC:POPE:POPG) | ||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3 | ||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm |
Image recording | Average exposure time: 2 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 16062 |
Image scans | Width: 5760 / Height: 4092 |
-Processing
EM software |
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CTF correction | Type: NONE | ||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 6558023 | ||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.58 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 778428 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||
Atomic model building | Space: REAL | ||||||||||||||||||||||||||||||||||||
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