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- EMDB-47491: Cryo-EM structure of the human P2X7 receptor in the ATP-bound ope... -

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Basic information

Entry
Database: EMDB / ID: EMD-47491
TitleCryo-EM structure of the human P2X7 receptor in the ATP-bound open state
Map dataSharpened map for human P2X7 in the ATP-bound desensitized state
Sample
  • Complex: Membrane protein
    • Protein or peptide: P2X purinoceptor 7
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: ZINC ION
  • Ligand: PALMITIC ACID
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: water
KeywordsMembrane Protein / Ion Channel / Ligand-Gated Ion Channel / P2X Receptor / P2XR / Allosteric Antagonist / Agonist
Function / homology
Function and homology information


positive regulation of bleb assembly / NAD transport / gamma-aminobutyric acid secretion / phagolysosome assembly / phospholipid transfer to membrane / positive regulation of cytoskeleton organization / positive regulation of monoatomic ion transmembrane transport / Platelet homeostasis / purinergic nucleotide receptor signaling pathway / positive regulation of gamma-aminobutyric acid secretion ...positive regulation of bleb assembly / NAD transport / gamma-aminobutyric acid secretion / phagolysosome assembly / phospholipid transfer to membrane / positive regulation of cytoskeleton organization / positive regulation of monoatomic ion transmembrane transport / Platelet homeostasis / purinergic nucleotide receptor signaling pathway / positive regulation of gamma-aminobutyric acid secretion / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / collagen metabolic process / positive regulation of interleukin-1 alpha production / pore complex assembly / negative regulation of cell volume / positive regulation of prostaglandin secretion / plasma membrane phospholipid scrambling / T cell apoptotic process / mitochondrial depolarization / Elevation of cytosolic Ca2+ levels / bleb assembly / vesicle budding from membrane / positive regulation of T cell apoptotic process / prostaglandin secretion / bleb / response to fluid shear stress / cellular response to dsRNA / glutamate secretion / ceramide biosynthetic process / negative regulation of bone resorption / positive regulation of glutamate secretion / skeletal system morphogenesis / positive regulation of macrophage cytokine production / response to zinc ion / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / sodium channel activity / protein homotrimerization / response to ATP / cellular response to ATP / positive regulation of mitochondrial depolarization / positive regulation of NLRP3 inflammasome complex assembly / T cell homeostasis / membrane protein ectodomain proteolysis / response to electrical stimulus / The NLRP3 inflammasome / positive regulation of calcium ion transport into cytosol / synaptic vesicle exocytosis / protein secretion / membrane depolarization / T cell proliferation / positive regulation of bone mineralization / monoatomic ion channel activity / potassium channel activity / response to mechanical stimulus / Purinergic signaling in leishmaniasis infection / regulation of sodium ion transport / extrinsic apoptotic signaling pathway / negative regulation of MAPK cascade / release of sequestered calcium ion into cytosol / homeostasis of number of cells within a tissue / sensory perception of pain / reactive oxygen species metabolic process / positive regulation of glycolytic process / response to ischemia / positive regulation of interleukin-1 beta production / positive regulation of protein secretion / T cell mediated cytotoxicity / protein catabolic process / neuromuscular junction / apoptotic signaling pathway / mitochondrion organization / lipopolysaccharide binding / calcium-mediated signaling / protein processing / response to calcium ion / positive regulation of interleukin-6 production / positive regulation of T cell mediated cytotoxicity / calcium ion transmembrane transport / cell morphogenesis / cell-cell junction / MAPK cascade / presynapse / response to lipopolysaccharide / positive regulation of MAPK cascade / cell surface receptor signaling pathway / postsynapse / defense response to Gram-positive bacterium / response to xenobiotic stimulus / inflammatory response / signaling receptor binding / external side of plasma membrane / neuronal cell body / positive regulation of gene expression / mitochondrion / ATP binding / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
P2X purinoreceptor 7, intracellular domain / P2X purinoreceptor 7 intracellular domain / P2X7 purinoceptor / : / ATP P2X receptors signature. / ATP P2X receptor / P2X purinoreceptor / P2X purinoreceptor extracellular domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.95 Å
AuthorsOken AC / Turcu AL / Vazquez S / Mansoor SE
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R00HL138129 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)DP2GM149551 United States
CitationJournal: Nat Commun / Year: 2025
Title: A polycyclic scaffold identified by structure-based drug design effectively inhibits the human P2X7 receptor.
Authors: Adam C Oken / Andreea L Turcu / Eva Tzortzini / Kyriakos Georgiou / Jessica Nagel / Franka G Westermann / Marta Barniol-Xicota / Jonas Seidler / Ga-Ram Kim / So-Deok Lee / Annette Nicke / ...Authors: Adam C Oken / Andreea L Turcu / Eva Tzortzini / Kyriakos Georgiou / Jessica Nagel / Franka G Westermann / Marta Barniol-Xicota / Jonas Seidler / Ga-Ram Kim / So-Deok Lee / Annette Nicke / Yong-Chul Kim / Christa E Müller / Antonios Kolocouris / Santiago Vázquez / Steven E Mansoor /
Abstract: The P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits ...The P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits of blocking overactive signaling, no P2X7 receptor antagonists have been approved for clinical use. Understanding species-specific pharmacological effects of existing antagonists has been challenging, in part due to the dearth of molecular information on receptor orthologs. Here, to identify distinct molecular features in the human receptor, we determine high-resolution cryo-EM structures of the full-length wild-type human P2X7 receptor in apo closed and ATP-bound open state conformations and draw comparisons with structures of other orthologs. We also report a cryo-EM structure of the human receptor in complex with an adamantane-based inhibitor, which we leverage, in conjunction with functional data and molecular dynamics simulations, to design a potent and selective antagonist with a unique polycyclic scaffold. Functional and structural analysis reveal how this optimized ligand, termed UB-MBX-46, interacts with the classical allosteric pocket of the human P2X7 receptor with subnanomolar potency and high selectivity, revealing its significant therapeutic potential.
History
DepositionOct 23, 2024-
Header (metadata) releaseSep 24, 2025-
Map releaseSep 24, 2025-
UpdateSep 24, 2025-
Current statusSep 24, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47491.png

Downloads & links

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Map

FileDownload / File: emd_47491.map.gz / Format: CCP4 / Size: 824 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map for human P2X7 in the ATP-bound desensitized state
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 600 pix.
= 388.8 Å		0.65 Å/pix.
x 600 pix.
= 388.8 Å		0.65 Å/pix.
x 600 pix.
= 388.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.648 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.095
Minimum - Maximum-0.6692496 - 0.92371595
Average (Standard dev.)0.00009356131 (±0.010819359)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions600600600
Spacing600600600
CellA=B=C: 388.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_47491_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened map for human P2X7 in the ATP-bound desensitized state

Fileemd_47491_additional_1.map
AnnotationUnsharpened map for human P2X7 in the ATP-bound desensitized state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B for human P2X7 in the ATP-bound desensitized state

Fileemd_47491_half_map_1.map
AnnotationHalf map B for human P2X7 in the ATP-bound desensitized state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A for human P2X7 in the ATP-bound desensitized state

Fileemd_47491_half_map_2.map
AnnotationHalf map A for human P2X7 in the ATP-bound desensitized state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Membrane protein

EntireName: Membrane protein
Components
  • Complex: Membrane protein
    • Protein or peptide: P2X purinoceptor 7
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: ZINC ION
  • Ligand: PALMITIC ACID
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: water

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Supramolecule #1: Membrane protein

SupramoleculeName: Membrane protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: P2X purinoceptor 7

MacromoleculeName: P2X purinoceptor 7 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 68.67182 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPACCSCSDV FQYETNKVTR IQSMNYGTIK WFFHVIIFSY VCFALVSDKL YQRKEPVISS VHTKVKGIAE VKEEIVENGV KKLVHSVFD TADYTFPLQG NSFFVMTNFL KTEGQEQRLC PEYPTRRTLC SSDRGCKKGW MDPQSKGIQT GRCVVYEGNQ K TCEVSAWC ...String:
MPACCSCSDV FQYETNKVTR IQSMNYGTIK WFFHVIIFSY VCFALVSDKL YQRKEPVISS VHTKVKGIAE VKEEIVENGV KKLVHSVFD TADYTFPLQG NSFFVMTNFL KTEGQEQRLC PEYPTRRTLC SSDRGCKKGW MDPQSKGIQT GRCVVYEGNQ K TCEVSAWC PIEAVEEAPR PALLNSAENF TVLIKNNIDF PGHNYTTRNI LPGLNITCTF HKTQNPQCPI FRLGDIFRET GD NFSDVAI QGGIMGIEIY WDCNLDRWFH HCRPKYSFRR LDDKTTNVSL YPGYNFRYAK YYKENNVEKR TLIKVFGIRF DIL VFGTGG KFDIIQLVVY IGSTLSYFGL AAVFIDFLID TYSSNCCRSH IYPWCKCCQP CVVNEYYYRK KCESIVEPKP TLKY VSFVD ESHIRMVNQQ LLGRSLQDVK GQEVPRPAMD FTDLSRLPLA LHDTPPIPGQ PEEIQLLRKE ATPRSRDSPV WCQCG SCLP SQLPESHRCL EELCCRKKPG ACITTSELFR KLVLSRHVLQ FLLLYQEPLL ALDVDSTNSR LRHCAYRCYA TWRFGS QDM ADFAILPSCC RWRIRKEFPK SEGQYSGFKS PY

UniProtKB: P2X purinoceptor 7

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Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 12 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #3: GUANOSINE-5'-DIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 3 / Formula: GDP
Molecular weightTheoretical: 443.201 Da
Chemical component information

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 6 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #5: PALMITIC ACID

MacromoleculeName: PALMITIC ACID / type: ligand / ID: 5 / Number of copies: 15 / Formula: PLM
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 256.424 Da
Chemical component information

ChemComp-PLM:
PALMITIC ACID

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Macromolecule #6: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 6 / Number of copies: 3 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 68 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 8721 / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6u9w

Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 156509
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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