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- PDB-8gfa: Cryo-EM structure of human TRPV1 in complex with the analgesic dr... -
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Open data
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Basic information
Entry | Database: PDB / ID: 8gfa | ||||||||||||||||||
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Title | Cryo-EM structure of human TRPV1 in complex with the analgesic drug SB-366791 | ||||||||||||||||||
![]() | Transient receptor potential cation channel subfamily V member 1 | ||||||||||||||||||
![]() | MEMBRANE PROTEIN / transient receptor potential V family member 1 / TRP / human / channel / inhibition / antagonist / TRPV1 / TRP channels / pain / analgesic / drug / SB-366791 / thermo-TRP / temperature sensation / vanilloid / GDN / detergent / glyco-diosgenin | ||||||||||||||||||
Function / homology | ![]() 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 / excitatory extracellular ligand-gated monoatomic ion channel activity / fever generation / thermoception / detection of temperature stimulus involved in thermoception / glutamate secretion / negative regulation of systemic arterial blood pressure / chloride channel regulator activity / dendritic spine membrane / TRP channels / cellular response to ATP / negative regulation of heart rate / cellular response to alkaloid / calcium ion import across plasma membrane / diet induced thermogenesis / behavioral response to pain / intracellularly gated calcium channel activity / detection of temperature stimulus involved in sensory perception of pain / 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 / transmembrane signaling receptor activity / positive regulation of nitric oxide biosynthetic process / cellular response to tumor necrosis factor / positive regulation of cytosolic calcium ion concentration / cellular response to heat / 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 | ||||||||||||||||||
Biological species | ![]() | ||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.29 Å | ||||||||||||||||||
![]() | Neuberger, A. / Nadezhdin, K.D. / Sobolevsky, A.I. | ||||||||||||||||||
Funding support | ![]() ![]()
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![]() | ![]() 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: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 855.4 KB | Display | ![]() |
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PDB format | ![]() | 716.7 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 29983MC ![]() 8gf8C ![]() 8gf9C C: citing same article ( M: map data used to model this data |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Components
-Protein , 1 types, 4 molecules ABCD
#1: Protein | Mass: 124575.281 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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-Non-polymers , 5 types, 151 molecules ![](data/chem/img/POV.gif)
![](data/chem/img/ZEI.gif)
![](data/chem/img/DU0.gif)
![](data/chem/img/NA.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/ZEI.gif)
![](data/chem/img/DU0.gif)
![](data/chem/img/NA.gif)
![](data/chem/img/HOH.gif)
#2: Chemical | ChemComp-POV / ( #3: Chemical | ChemComp-ZEI / ( #4: Chemical | ChemComp-DU0 / #5: Chemical | #6: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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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 |
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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: ![]() | ||||||||||||||||||||||||||||||
Source (recombinant) | Organism: ![]() | ||||||||||||||||||||||||||||||
Buffer solution | pH: 8 | ||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: human TRPV1 | ||||||||||||||||||||||||||||||
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 |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 750 nm / Cs: 2.7 mm |
Image recording | Average exposure time: 1.87 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4188 |
Image scans | Width: 5760 / Height: 4092 |
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Processing
EM software |
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CTF correction | Type: NONE | ||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 1988636 | ||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.29 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 67470 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||
Atomic model building | Space: REAL | ||||||||||||||||||||||||||||||||||||
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