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- PDB-9e3o: Cryo-EM structure of the human P2X7 receptor in the UB-ALT-P30-bo... -

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Basic information

Entry
Database: PDB / ID: 9e3o
TitleCryo-EM structure of the human P2X7 receptor in the UB-ALT-P30-bound inhibited 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 / Platelet homeostasis / phagolysosome assembly / positive regulation of cytoskeleton organization / phospholipid transfer to membrane / positive regulation of monoatomic ion transmembrane transport / purinergic nucleotide receptor signaling pathway / gamma-aminobutyric acid secretion / extracellularly ATP-gated monoatomic cation channel activity ...positive regulation of bleb assembly / NAD transport / Platelet homeostasis / phagolysosome assembly / positive regulation of cytoskeleton organization / phospholipid transfer to membrane / positive regulation of monoatomic ion transmembrane transport / purinergic nucleotide receptor signaling pathway / gamma-aminobutyric acid secretion / extracellularly ATP-gated monoatomic cation channel activity / pore complex assembly / positive regulation of interleukin-1 alpha production / purinergic nucleotide receptor activity / positive regulation of gamma-aminobutyric acid secretion / bleb / Elevation of cytosolic Ca2+ levels / plasma membrane phospholipid scrambling / negative regulation of cell volume / collagen metabolic process / positive regulation of prostaglandin secretion / T cell apoptotic process / bleb assembly / response to fluid shear stress / mitochondrial depolarization / vesicle budding from membrane / ceramide biosynthetic process / positive regulation of T cell apoptotic process / prostaglandin secretion / cellular response to dsRNA / glutamate secretion / positive regulation of glutamate secretion / negative regulation of bone resorption / positive regulation of macrophage cytokine production / skeletal system morphogenesis / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / response to zinc ion / response to ATP / positive regulation of mitochondrial depolarization / positive regulation of NLRP3 inflammasome complex assembly / sodium channel activity / cellular response to ATP / protein homotrimerization / T cell homeostasis / monoatomic ion channel activity / positive regulation of calcium ion transport into cytosol / membrane protein ectodomain proteolysis / The NLRP3 inflammasome / protein secretion / synaptic vesicle exocytosis / response to electrical stimulus / membrane depolarization / potassium channel activity / positive regulation of bone mineralization / response to mechanical stimulus / T cell proliferation / Purinergic signaling in leishmaniasis infection / regulation of sodium ion transport / negative regulation of MAPK cascade / extrinsic apoptotic signaling pathway / release of sequestered calcium ion into cytosol / sensory perception of pain / homeostasis of number of cells within a tissue / 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 / mitochondrion organization / neuromuscular junction / apoptotic signaling pathway / lipopolysaccharide binding / protein catabolic process / calcium-mediated signaling / T cell mediated cytotoxicity / response to calcium ion / calcium ion transmembrane transport / protein processing / positive regulation of interleukin-6 production / positive regulation of T cell mediated cytotoxicity / cell morphogenesis / cell-cell junction / presynapse / MAPK cascade / response to lipopolysaccharide / cell surface receptor signaling pathway / postsynapse / positive regulation of MAPK cascade / 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 / identical protein binding / membrane / 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
: / 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: 2.76 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
B: P2X purinoceptor 7
C: P2X purinoceptor 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)218,94851
Polymers206,0153
Non-polymers12,93348
Water3,189177
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 / Sugars , 2 types, 12 molecules ABC

#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 / Production host: Homo sapiens (human) / References: UniProt: Q99572
#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.: 9 / 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, 216 molecules

#2: Chemical ChemComp-A1BD8 / (3s,5s,7s)-N'-(2-chlorophenyl)adamantane-1-carbohydrazide


Mass: 304.814 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C17H21ClN2O / Feature type: SUBJECT OF INVESTIGATION
#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 / Production host: Homo sapiens (human) / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 177 / 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
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: 1500 nm / Nominal defocus min: 900 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 43 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 14463
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: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 194103 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00914262
ELECTRON MICROSCOPYf_angle_d0.71419308
ELECTRON MICROSCOPYf_dihedral_angle_d9.7112172
ELECTRON MICROSCOPYf_chiral_restr0.0492058
ELECTRON MICROSCOPYf_plane_restr0.0052376

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