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- EMDB-45153: Cryo-EM structure of the human P2X1 receptor in the ATP-bound des... -
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Basic information
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Title | Cryo-EM structure of the human P2X1 receptor in the ATP-bound desensitized state | |||||||||
![]() | Sharpened map for hP2X1 in the ATP-bound desensitized state | |||||||||
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![]() | Membrane Protein / Ion Channel / Ligand-gated Ion Channel / P2X Receptor / Allosteric Antagonist | |||||||||
Function / homology | ![]() regulation of vascular associated smooth muscle contraction / Platelet homeostasis / insemination / positive regulation of calcium ion import across plasma membrane / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / suramin binding / serotonin secretion by platelet / ligand-gated calcium channel activity / Elevation of cytosolic Ca2+ levels ...regulation of vascular associated smooth muscle contraction / Platelet homeostasis / insemination / positive regulation of calcium ion import across plasma membrane / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / suramin binding / serotonin secretion by platelet / ligand-gated calcium channel activity / Elevation of cytosolic Ca2+ levels / regulation of presynaptic cytosolic calcium ion concentration / ceramide biosynthetic process / response to ATP / regulation of synaptic vesicle exocytosis / neuronal action potential / specific granule membrane / monoatomic cation channel activity / monoatomic ion transport / presynaptic active zone membrane / secretory granule membrane / synaptic transmission, glutamatergic / calcium ion transmembrane transport / platelet activation / regulation of blood pressure / postsynaptic membrane / membrane raft / external side of plasma membrane / apoptotic process / Neutrophil degranulation / protein-containing complex binding / glutamatergic synapse / signal transduction / protein-containing complex / ATP binding / identical protein binding / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.42 Å | |||||||||
![]() | Oken AC / Lisi NE / Ditter IA / Shi H / Mansoor SE | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Cryo-EM structures of the human P2X1 receptor reveal subtype-specific architecture and antagonism by supramolecular ligand-binding. Authors: Adam C Oken / Nicolas E Lisi / Ismayn A Ditter / Haoyuan Shi / Nadia A Nechiporuk / Steven E Mansoor / ![]() Abstract: P2X receptors are a family of seven trimeric non-selective cation channels that are activated by extracellular ATP to play roles in the cardiovascular, neuronal, and immune systems. Although it is ...P2X receptors are a family of seven trimeric non-selective cation channels that are activated by extracellular ATP to play roles in the cardiovascular, neuronal, and immune systems. Although it is known that the P2X1 receptor subtype has increased sensitivity to ATP and fast desensitization kinetics, an underlying molecular explanation for these subtype-selective features is lacking. Here we report high-resolution cryo-EM structures of the human P2X1 receptor in the apo closed, ATP-bound desensitized, and the high-affinity antagonist NF449-bound inhibited states. The apo closed and ATP-bound desensitized state structures of human P2X1 define subtype-specific properties such as distinct pore architecture and ATP-interacting residues. The NF449-bound inhibited state structure of human P2X1 reveals that NF449 has a unique dual-ligand supramolecular binding mode at the interface of neighboring protomers, inhibiting channel activation by overlapping with the canonical P2X receptor ATP-binding site. Altogether, these data define the molecular pharmacology of the human P2X1 receptor laying the foundation for structure-based drug design. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 226.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 24.6 KB 24.6 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 19.8 KB | Display | ![]() |
Images | ![]() | 118.9 KB | ||
Masks | ![]() | 244.1 MB | ![]() | |
Filedesc metadata | ![]() | 6.8 KB | ||
Others | ![]() ![]() ![]() ![]() | 205 MB 221.5 MB 226.6 MB 226.6 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 871.2 KB | Display | ![]() |
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Full document | ![]() | 870.9 KB | Display | |
Data in XML | ![]() | 24.8 KB | Display | |
Data in CIF | ![]() | 33.2 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 9c2bMC ![]() 9c2aC ![]() 9c2cC 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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Map
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Annotation | Sharpened map for hP2X1 in the ATP-bound desensitized state | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.6488 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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Density Histograms |
-Additional map: DeepEMhancer sharpened map for hP2X1 in the ATP-bound...
File | emd_45153_additional_1.map | ||||||||||||
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Annotation | DeepEMhancer sharpened map for hP2X1 in the ATP-bound desensitized state | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Unsharpened map for hP2X1 in the ATP-bound desensitized state
File | emd_45153_additional_2.map | ||||||||||||
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Annotation | Unsharpened map for hP2X1 in the ATP-bound desensitized state | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map B for hP2X1 in the ATP-bound desensitized state
File | emd_45153_half_map_1.map | ||||||||||||
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Annotation | Half map B for hP2X1 in the ATP-bound desensitized state | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map A for hP2X1 in the ATP-bound desensitized state
File | emd_45153_half_map_2.map | ||||||||||||
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Annotation | Half map A for hP2X1 in the ATP-bound desensitized state | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Membrane protein
Entire | Name: Membrane protein |
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Components |
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-Supramolecule #1: Membrane protein
Supramolecule | Name: Membrane protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: P2X purinoceptor 1
Macromolecule | Name: P2X purinoceptor 1 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 45.038957 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MARRFQEELA AFLFEYDTPR MVLVRNKKVG VIFRLIQLVV LVYVIGWVFL YEKGYQTSSG LISSVSVKLK GLAVTQLPGL GPQVWDVAD YVFPAQGDNS FVVMTNFIVT PKQTQGYCAE HPEGGICKED SGCTPGKAKR KAQGIRTGKC VAFNDTVKTC E IFGWCPVE ...String: MARRFQEELA AFLFEYDTPR MVLVRNKKVG VIFRLIQLVV LVYVIGWVFL YEKGYQTSSG LISSVSVKLK GLAVTQLPGL GPQVWDVAD YVFPAQGDNS FVVMTNFIVT PKQTQGYCAE HPEGGICKED SGCTPGKAKR KAQGIRTGKC VAFNDTVKTC E IFGWCPVE VDDDIPRPAL LREAENFTLF IKNSISFPRF KVNRRNLVEE VNAAHMKTCL FHKTLHPLCP VFQLGYVVQE SG QNFSTLA EKGGVVGITI DWHCDLDWHV RHCRPIYEFH GLYEEKNLSP GFNFRFARHF VENGTNYRHL FKVFGIRFDI LVD GKAGKF DIIPTMTTIG SGIGIFGVAT VLCDLLLLHI LPKRHYYKQK KFKYAEDMGP GAAERDLAAT SSTLGLQENM RTS UniProtKB: P2X purinoceptor 1 |
-Macromolecule #4: MAGNESIUM ION
Macromolecule | Name: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 3 / Formula: MG |
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Molecular weight | Theoretical: 24.305 Da |
-Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 3 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #6: ADENOSINE-5'-TRIPHOSPHATE
Macromolecule | Name: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 6 / Number of copies: 3 / Formula: ATP |
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Molecular weight | Theoretical: 507.181 Da |
Chemical component information | ![]() ChemComp-ATP: |
-Macromolecule #7: water
Macromolecule | Name: water / type: ligand / ID: 7 / Number of copies: 141 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7 |
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Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number real images: 4091 / Average electron dose: 44.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 130000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |