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- EMDB-29981: Cryo-EM structure of human TRPV1 in cNW11 nanodisc and soybean lipids -
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Open data
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Basic information
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Title | Cryo-EM structure of human TRPV1 in cNW11 nanodisc and soybean lipids | ||||||||||||||||||
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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 | single particle reconstruction / cryo EM / Resolution: 2.9 Å | ||||||||||||||||||
![]() | Neuberger A / Nadezhdin KD / Sobolevsky AI | ||||||||||||||||||
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
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 19.3 KB 19.3 KB | Display Display | ![]() |
Images | ![]() | 80 KB | ||
Others | ![]() ![]() | 58.9 MB 58.9 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8gf8MC ![]() 8gf9C ![]() 8gfaC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.825 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_29981_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_29981_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : sample 1
Entire | Name: sample 1 |
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Components |
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-Supramolecule #1: sample 1
Supramolecule | Name: sample 1 / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 94.97 KDa |
-Macromolecule #1: Transient receptor potential cation channel subfamily V member 1
Macromolecule | Name: Transient receptor potential cation channel subfamily V member 1 type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 124.575281 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MTSKKWSSTD LGAAADPLQK DTCPDPLDGD PNSRPPPAKP QLSTAKSRTR LFGKGDSEEA FPVDCPHEEG ELDSCPTITV SPVITIQRP GDGPTGARLL SQDSVAASTE KTLRLYDRRS IFEAVAQNNC QDLESLLLFL QKSKKHLTDN EFKDPETGKT C LLKAMLNL ...String: MTSKKWSSTD LGAAADPLQK DTCPDPLDGD PNSRPPPAKP QLSTAKSRTR LFGKGDSEEA FPVDCPHEEG ELDSCPTITV SPVITIQRP GDGPTGARLL SQDSVAASTE KTLRLYDRRS IFEAVAQNNC QDLESLLLFL QKSKKHLTDN EFKDPETGKT C LLKAMLNL HDGQNTTIPL LLEIARQTDS LKELVNASYT DSYYKGQTAL HIAIERRNMA LVTLLVENGA DVQAAAHGDF FK KTKGRPG FYFGELPLSL AACTNQLGIV KFLLQNSWQT ADISARDSVG NTVLHALVEV ADNTADNTKF VTSMYNEILM LGA KLHPTL KLEELTNKKG MTPLALAAGT GKIGVLAYIL QREIQEPECR HLSRKFTEWA YGPVHSSLYD LSCIDTCEKN SVLE VIAYS SSETPNRHDM LLVEPLNRLL QDKWDRFVKR IFYFNFLVYC LYMIIFTMAA YYRPVDGLPP FKMEKTGDYF RVTGE ILSV LGGVYFFFRG IQYFLQRRPS MKTLFVDSYS EMLFFLQSLF MLATVVLYFS HLKEYVASMV FSLALGWTNM LYYTRG FQQ MGIYAVMIEK MILRDLCRFM FVYIVFLFGF STAVVTLIED GKNDSLPSES TSHRWRGPAC RPPDSSYNSL YSTCLEL FK FTIGMGDLEF TENYDFKAVF IILLLAYVIL TYILLLNMLI ALMGETVNKI AQESKNIWKL QRAITILDTE KSFLKCMR K AFRSGKLLQV GYTPDGKDDY RWCFRVDEVN WTTWNTNVGI INEDPGNCEG VKRTLSFSLR SSRVSGRHWK NFALVPLLR EASARDRQSA QPEEVYLRQF SGSLKPEDAE VFKSPAASGE KLVPRGSAAA AVSKGEELFT GVVPILVELD GDVNGHKFSV SGEGEGDAT YGKLTLKFIC TTGKLPVPWP TLVTTLTYGV QCFSRYPDHM KQHDFFKSAM PEGYVQERTI FFKDDGNYKT R AEVKFEGD TLVNRIELKG IDFKEDGNIL GHKLEYNYNS HNVYIMADKQ KNGIKVNFKI RHNIEDGSVQ LADHYQQNTP IG DGPVLLP DNHYLSTQSK LSKDPNEKRD HMVLLEFVTA AGITLGMDEL YKSGLRSWSH PQFEK |
-Macromolecule #2: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...
Macromolecule | Name: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate type: ligand / ID: 2 / Number of copies: 36 / Formula: POV |
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Molecular weight | Theoretical: 760.076 Da |
Chemical component information | ![]() ChemComp-POV: |
-Macromolecule #3: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxyc...
Macromolecule | Name: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctadecanoate type: ligand / ID: 3 / Number of copies: 4 / Formula: 8IJ |
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Molecular weight | Theoretical: 867.138 Da |
Chemical component information | ![]() ChemComp-8IJ: |
-Macromolecule #4: SODIUM ION
Macromolecule | Name: SODIUM ION / type: ligand / ID: 4 / Number of copies: 2 |
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Molecular weight | Theoretical: 22.99 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 2.5 mg/mL | ||||||||||||
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Buffer | pH: 8 Component:
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Grid | Model: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE | ||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV | ||||||||||||
Details | human TRPV1 reconstituted in cNW11 lipid nanodisc (soybean lipid extract) |
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Electron microscopy
Microscope | TFS KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 1 / Number real images: 19303 / Average exposure time: 2.8 sec. / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.75 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Particle selection | Number selected: 8994098 |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 323292 |
Initial angle assignment | Type: OTHER |
Final angle assignment | Type: OTHER |
-Atomic model buiding 1
Refinement | Space: REAL |
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Output model | ![]() PDB-8gf8: |