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- EMDB-47494: Cryo-EM structure of the mouse P2X7 receptor in the apo closed state -

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Basic information

Entry
Database: EMDB / ID: EMD-47494
TitleCryo-EM structure of the mouse P2X7 receptor in the apo closed state
Map dataSharpened map for mouse P2X7 in the apo closed state
Sample
  • Complex: Membrane protein
    • Protein or peptide: P2X purinoceptor 7
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: ZINC ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: PALMITIC ACID
  • Ligand: SODIUM ION
  • Ligand: water
KeywordsMembrane Protein / Ion Channel / Ligand-Gated Ion Channel / P2X Receptor / P2XR / Allosteric Antagonist / Agonist
Function / homology
Function and homology information


Platelet homeostasis / NAD transport / positive regulation of lymphocyte apoptotic process / phospholipid transfer to membrane / regulation of presynaptic dense core granule exocytosis / Elevation of cytosolic Ca2+ levels / positive regulation of bleb assembly / The NLRP3 inflammasome / phagolysosome assembly / positive regulation of cytoskeleton organization ...Platelet homeostasis / NAD transport / positive regulation of lymphocyte apoptotic process / phospholipid transfer to membrane / regulation of presynaptic dense core granule exocytosis / Elevation of cytosolic Ca2+ levels / positive regulation of bleb assembly / The NLRP3 inflammasome / phagolysosome assembly / positive regulation of cytoskeleton organization / positive regulation of monoatomic ion transmembrane transport / plasma membrane organization / purinergic nucleotide receptor signaling pathway / positive regulation of prostaglandin secretion / positive regulation of interleukin-1 alpha production / collagen metabolic process / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / bleb assembly / ATP export / positive regulation of catalytic activity / pore complex assembly / negative regulation of cell volume / positive regulation of gamma-aminobutyric acid secretion / plasma membrane phospholipid scrambling / response to fluid shear stress / vesicle budding from membrane / programmed cell death / bleb / ceramide biosynthetic process / negative regulation of bone resorption / T cell proliferation / positive regulation of ossification / cell volume homeostasis / skeletal system morphogenesis / cellular response to dsRNA / phospholipid translocation / response to zinc ion / T cell homeostasis / positive regulation of bone mineralization / positive regulation of glutamate secretion / response to ATP / protein homotrimerization / positive regulation of MAP kinase activity / regulation of sodium ion transport / sodium channel activity / membrane protein ectodomain proteolysis / positive regulation of mitochondrial depolarization / positive regulation of calcium ion transport into cytosol / positive regulation of NLRP3 inflammasome complex assembly / response to electrical stimulus / synaptic vesicle exocytosis / homeostasis of number of cells within a tissue / membrane depolarization / response to mechanical stimulus / potassium channel activity / monoatomic cation transport / extrinsic apoptotic signaling pathway / response to bacterium / neuronal action potential / release of sequestered calcium ion into cytosol / negative regulation of MAPK cascade / reactive oxygen species metabolic process / sensory perception of pain / protein catabolic process / positive regulation of glycolytic process / positive regulation of T cell mediated cytotoxicity / apoptotic signaling pathway / positive regulation of protein secretion / positive regulation of cytokine production / positive regulation of interleukin-1 beta production / protein serine/threonine kinase activator activity / mitochondrion organization / neuromuscular junction / lipopolysaccharide binding / protein processing / cell morphogenesis / response to calcium ion / positive regulation of interleukin-6 production / positive regulation of protein phosphorylation / gene expression / calcium ion transmembrane transport / calcium ion transport / terminal bouton / cell-cell junction / nuclear envelope / response to lipopolysaccharide / channel activity / signaling receptor activity / scaffold protein binding / positive regulation of MAPK cascade / protein phosphorylation / cell surface receptor signaling pathway / postsynapse / defense response to Gram-positive bacterium / response to xenobiotic stimulus / positive regulation of apoptotic process / inflammatory response / copper ion binding / external side of plasma membrane
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 speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.53 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_47494.png

Downloads & links

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Map

FileDownload / File: emd_47494.map.gz / Format: CCP4 / Size: 824 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map for mouse P2X7 in the apo closed 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: 0.16
Minimum - Maximum-1.1547215 - 1.4698818
Average (Standard dev.)0.00026103228 (±0.018822849)
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_47494_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 mouse P2X7 in the apo closed state

Fileemd_47494_additional_1.map
AnnotationUnsharpened map for mouse P2X7 in the apo closed state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B for mouse P2X7 in the apo closed state

Fileemd_47494_half_map_1.map
AnnotationHalf map B for mouse P2X7 in the apo closed state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A for mouse P2X7 in the apo closed state

Fileemd_47494_half_map_2.map
AnnotationHalf map A for mouse P2X7 in the apo closed 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: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: ZINC ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: PALMITIC ACID
  • Ligand: SODIUM ION
  • 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: Mus musculus (house mouse)

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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: Mus musculus (house mouse)
Molecular weightTheoretical: 68.476148 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPACCSWNDV LQYETNKVTR IQSTNYGTVK WVLHMIVFSY ISFALVSDKL YQRKEPVISS VHTKVKGIAE VTENVTEGGV TKLGHSIFD TADYTFPLQG NSFFVMTNYV KSEGQVQTLC PEYPRRGAQC SSDRRCKKGW MDPQSKGIQT GRCVPYDKTR K TCEVSAWC ...String:
MPACCSWNDV LQYETNKVTR IQSTNYGTVK WVLHMIVFSY ISFALVSDKL YQRKEPVISS VHTKVKGIAE VTENVTEGGV TKLGHSIFD TADYTFPLQG NSFFVMTNYV KSEGQVQTLC PEYPRRGAQC SSDRRCKKGW MDPQSKGIQT GRCVPYDKTR K TCEVSAWC PTEEEKEAPR PALLRSAENF TVLIKNNIHF PGHNYTTRNI LPTMNGSCTF HKTWDPQCSI FRLGDIFQEA GE NFTEVAV QGGIMGIEIY WDCNLDSWSH HCRPRYSFRR LDDKNTDESF VPGYNFRYAK YYKENNVEKR TLIKAFGIRF DIL VFGTGG KFDIIQLVVY IGSTLSYFGL ATVCIDLLIN TYSSAFCRSG VYPYCKCCEP CTVNEYYYRK KCESIMEPKP TLKY VSFVD EPHIRMVDQQ LLGKSLQVVK GQEVPRPQMD FSDLSRLSLS LHDSPLTPGQ SEEIQLLHEE VAPKSGDSPS WCQCG NCLP SRLPEQRRAL EELCCRRKPG RCITTSKLFH KLVLSRDTLQ LLLLYQDPLL VLGEEATNSR LRHRAYRCYA TWRFGS QDM ADFAILPSCC RWRIRKEFPK TEGQYSGFKY PY

UniProtKB: P2X purinoceptor 7

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Macromolecule #2: GUANOSINE-5'-DIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / 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 #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 6 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #5: PALMITIC ACID

MacromoleculeName: PALMITIC ACID / type: ligand / ID: 5 / Number of copies: 15 / Formula: PLM
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 256.424 Da
Chemical component information

ChemComp-PLM:
PALMITIC ACID

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Macromolecule #6: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 6 / Number of copies: 1
Molecular weightTheoretical: 22.99 Da

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 193 / 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

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 15909 / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.9 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:

8tr5

Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.53 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 370251
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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