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Yorodumi- EMDB-38161: Structure of human TRPV1 in complex with antagonist --protein pur... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-38161 | |||||||||
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Title | Structure of human TRPV1 in complex with antagonist --protein purified without CHS | |||||||||
Map data | ||||||||||
Sample |
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Keywords | channel / MEMBRANE PROTEIN | |||||||||
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 / cellular response to ATP / negative regulation of heart rate / cellular response to alkaloid / calcium ion import across plasma membrane / behavioral response to pain / diet induced thermogenesis / 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 / calcium ion transmembrane transport / phosphoprotein binding / 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 | |||||||||
Biological species | Homo sapiens (human) / synthetic construct (others) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.55 Å | |||||||||
Authors | Fan J / Lei X | |||||||||
Funding support | China, 1 items
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Citation | Journal: Nat Commun / Year: 2024 Title: Structural basis of TRPV1 inhibition by SAF312 and cholesterol. Authors: Junping Fan / Han Ke / Jing Lei / Jin Wang / Makoto Tominaga / Xiaoguang Lei / Abstract: Transient Receptor Potential Vanilloid 1 (TRPV1) plays a central role in pain sensation and is thus an attractive pharmacological drug target. SAF312 is a potent, selective, and non-competitive ...Transient Receptor Potential Vanilloid 1 (TRPV1) plays a central role in pain sensation and is thus an attractive pharmacological drug target. SAF312 is a potent, selective, and non-competitive antagonist of TRPV1 and shows promising potential in treating ocular surface pain. However, the precise mechanism by which SAF312 inhibits TRPV1 remains poorly understood. Here, we present the cryo-EM structure of human TRPV1 in complex with SAF312, elucidating the structural foundation of its antagonistic effects on TRPV1. SAF312 binds to the vanilloid binding pocket, preventing conformational changes in S4 and S5 helices, which are essential for channel gating. Unexpectedly, a putative cholesterol was found to contribute to SAF312's inhibition. Complemented by mutagenesis experiments and molecular dynamics simulations, our research offers substantial mechanistic insights into the regulation of TRPV1 by SAF312, highlighting the interplay between the antagonist and cholesterol in modulating TRPV1 function. This work not only expands our understanding of TRPV1 inhibition by SAF312 but also lays the groundwork for further developments in the design and optimization of TRPV1-related therapies. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_38161.map.gz | 117.8 MB | EMDB map data format | |
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Header (meta data) | emd-38161-v30.xml emd-38161.xml | 14.7 KB 14.7 KB | Display Display | EMDB header |
Images | emd_38161.png | 63.9 KB | ||
Filedesc metadata | emd-38161.cif.gz | 6.1 KB | ||
Others | emd_38161_half_map_1.map.gz emd_38161_half_map_2.map.gz | 115.2 MB 115.2 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-38161 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-38161 | HTTPS FTP |
-Validation report
Summary document | emd_38161_validation.pdf.gz | 843.7 KB | Display | EMDB validaton report |
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Full document | emd_38161_full_validation.pdf.gz | 843.3 KB | Display | |
Data in XML | emd_38161_validation.xml.gz | 14 KB | Display | |
Data in CIF | emd_38161_validation.cif.gz | 16.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38161 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38161 | HTTPS FTP |
-Related structure data
Related structure data | 8x94MC 8jqrC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_38161.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.85 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_38161_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_38161_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : TRPV1
Entire | Name: TRPV1 |
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Components |
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-Supramolecule #1: TRPV1
Supramolecule | Name: TRPV1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 360 KDa |
-Macromolecule #1: Transient receptor potential cation channel subfamily V member 1,...
Macromolecule | Name: Transient receptor potential cation channel subfamily V member 1,Green fluorescent protein type: protein_or_peptide / ID: 1 Details: The section (840-842) is the cloning site.The domain (843-850) is PreScission Site.The domain (851-1084) is corresponding to this sfGFP (462-695 amino acids, GenBank: ALP48449.1). The domain ...Details: The section (840-842) is the cloning site.The domain (843-850) is PreScission Site.The domain (851-1084) is corresponding to this sfGFP (462-695 amino acids, GenBank: ALP48449.1). The domain (1085-1112) is the expression Tag. Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 125.297734 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MKKWSSTDLG AAADPLQKDT CPDPLDGDPN SRPPPAKPQL STAKSRTRLF GKGDSEEAFP VDCPHEEGEL DSCPTITVSP VITIQRPGD GPTGARLLSQ DSVAASTEKT LRLYDRRSIF EAVAQNNCQD LESLLLFLQK SKKHLTDNEF KDPETGKTCL L KAMLNLHD ...String: MKKWSSTDLG AAADPLQKDT CPDPLDGDPN SRPPPAKPQL STAKSRTRLF GKGDSEEAFP VDCPHEEGEL DSCPTITVSP VITIQRPGD GPTGARLLSQ DSVAASTEKT LRLYDRRSIF EAVAQNNCQD LESLLLFLQK SKKHLTDNEF KDPETGKTCL L KAMLNLHD GQNTTIPLLL EIARQTDSLK ELVNASYTDS YYKGQTALHI AIERRNMALV TLLVENGADV QAAAHGDFFK KT KGRPGFY FGELPLSLAA CTNQLGIVKF LLQNSWQTAD ISARDSVGNT VLHALVEVAD NTADNTKFVT SMYNEILMLG AKL HPTLKL EELTNKKGMT PLALAAGTGK IGVLAYILQR EIQEPECRHL SRKFTEWAYG PVHSSLYDLS CIDTCEKNSV LEVI AYSSS ETPNRHDMLL VEPLNRLLQD KWDRFVKRIF YFNFLVYCLY MIIFTMAAYY RPVDGLPPFK MEKTGDYFRV TGEIL SVLG GVYFFFRGIQ YFLQRRPSMK TLFVDSYSEM LFFLQSLFML ATVVLYFSHL KEYVASMVFS LALGWTNMLY YTRGFQ QMG IYAVMIEKMI LRDLCRFMFV YIVFLFGFST AVVTLIEDGK NDSLPSESTS HRWRGPACRP PDSSYNSLYS TCLELFK FT IGMGDLEFTE NYDFKAVFII LLLAYVILTY ILLLNMLIAL MGETVNKIAQ ESKNIWKLQR AITILDTEKS FLKCMRKA F RSGKLLQVGY TPDGKDDYRW CFRVDEVNWT TWNTNVGIIN EDPGNCEGVK RTLSFSLRSS RVSGRHWKNF ALVPLLREA SARDRQSAQP EEVYLRQFSG SLKPEDAEVF KSPAASGEKA AALEVLFQGP SKGEELFTGV VPILVELDGD VNGHKFSVRG EGEGDATNG KLTLKFICTT GKLPVPWPTL VTTLTYGVQC FSRYPDHMKR HDFFKSAMPE GYVQERTISF KDDGTYKTRA E VKFEGDTL VNRIELKGID FKEDGNILGH KLEYNFNSHN VYITADKQKN GIKANFKIRH NVEDGSVQLA DHYQQNTPIG DG PVLLPDN HYLSTQSVLS KDPNEKRDHM VLLEFVTAAG ITHGMDEWSH PQFEKGGGSG GGSGGSAWSH PQFEK UniProtKB: Transient receptor potential cation channel subfamily V member 1 |
-Macromolecule #2: 4-(7-Hydroxy-2-isopropyl-4-oxoquinazolin-3(4H)-yl)benzonitrile
Macromolecule | Name: 4-(7-Hydroxy-2-isopropyl-4-oxoquinazolin-3(4H)-yl)benzonitrile type: ligand / ID: 2 / Number of copies: 4 / Formula: EZI |
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Molecular weight | Theoretical: 305.331 Da |
-Macromolecule #3: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 4 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: OTHER |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.55 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 183350 |
Initial angle assignment | Type: RANDOM ASSIGNMENT |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |