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- PDB-9e3m: Cryo-EM structure of the human P2X7 receptor in the apo closed state -

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Basic information

Entry
Database: PDB / ID: 9e3m
TitleCryo-EM structure of the human P2X7 receptor in the apo closed state
ComponentsP2X purinoceptor 7
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 / Platelet homeostasis / positive regulation of monoatomic ion transmembrane transport / purinergic nucleotide receptor signaling pathway / extracellularly ATP-gated monoatomic cation channel activity ...positive regulation of bleb assembly / NAD transport / gamma-aminobutyric acid secretion / phagolysosome assembly / phospholipid transfer to membrane / positive regulation of cytoskeleton organization / Platelet homeostasis / positive regulation of monoatomic ion transmembrane transport / purinergic nucleotide receptor signaling pathway / extracellularly ATP-gated monoatomic cation channel activity / positive regulation of gamma-aminobutyric acid secretion / positive regulation of interleukin-1 alpha production / purinergic nucleotide receptor activity / collagen metabolic process / positive regulation of prostaglandin secretion / pore complex assembly / negative regulation of cell volume / T cell apoptotic process / plasma membrane phospholipid scrambling / 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 / glutamate secretion / cellular response to dsRNA / negative regulation of bone resorption / ceramide biosynthetic process / skeletal system morphogenesis / positive regulation of macrophage cytokine production / positive regulation of glutamate secretion / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / response to zinc ion / sodium channel activity / protein homotrimerization / response to ATP / cellular response to ATP / positive regulation of NLRP3 inflammasome complex assembly / positive regulation of mitochondrial depolarization / T cell homeostasis / membrane protein ectodomain proteolysis / The NLRP3 inflammasome / protein secretion / synaptic vesicle exocytosis / response to electrical stimulus / positive regulation of calcium ion transport into cytosol / membrane depolarization / T cell proliferation / positive regulation of bone mineralization / 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 / reactive oxygen species metabolic process / homeostasis of number of cells within a tissue / sensory perception of pain / positive regulation of glycolytic process / response to ischemia / positive regulation of protein secretion / positive regulation of interleukin-1 beta production / T cell mediated cytotoxicity / protein catabolic process / apoptotic signaling pathway / neuromuscular junction / mitochondrion organization / calcium-mediated signaling / lipopolysaccharide binding / 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 / GTP binding / mitochondrion / ATP binding / membrane / metal ion binding / identical protein binding / 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
GUANOSINE-5'-DIPHOSPHATE / PALMITIC ACID / CHOLESTEROL HEMISUCCINATE / P2X purinoceptor 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.48 Å
AuthorsOken, A.C. / Turcu, A.L. / Vazquez, S. / Mansoor, S.E.
Funding support United States, 2items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 24, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: P2X purinoceptor 7
C: P2X purinoceptor 7
B: P2X purinoceptor 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)219,93952
Polymers206,0153
Non-polymers13,92449
Water2,180121
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 3 molecules ACB

#1: Protein P2X purinoceptor 7 / P2X7 / ATP receptor / P2Z receptor / Purinergic receptor


Mass: 68671.820 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: P2RX7 / Cell line (production host): HEK293 GNTI- / Production host: Homo sapiens (human) / References: UniProt: Q99572

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Sugars , 2 types, 12 molecules

#2: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 6 types, 158 molecules

#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C31H50O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical...
ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 21
Source method: isolated from a genetically manipulated source
Formula: C16H32O2 / Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 GNTI- / Production host: Homo sapiens (human) / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na / Feature type: SUBJECT OF INVESTIGATION
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Membrane protein / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293 GNTI-
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 1400 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 42 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 8314
EM imaging opticsEnergyfilter slit width: 20 eV

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 2.48 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 187914 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00814313
ELECTRON MICROSCOPYf_angle_d0.83819371
ELECTRON MICROSCOPYf_dihedral_angle_d9.5542193
ELECTRON MICROSCOPYf_chiral_restr0.0512076
ELECTRON MICROSCOPYf_plane_restr0.0042391

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