[English] 日本語
Yorodumi
- PDB-9e3n: Cryo-EM structure of the human P2X7 receptor in the ATP-bound ope... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 9e3n
TitleCryo-EM structure of the human P2X7 receptor in the ATP-bound open 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 / 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 / purinergic nucleotide receptor activity / bleb assembly / pore complex assembly / negative regulation of cell volume ...positive regulation of bleb assembly / 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 / purinergic nucleotide receptor activity / bleb assembly / pore complex assembly / negative regulation of cell volume / plasma membrane phospholipid scrambling / Elevation of cytosolic Ca2+ levels / bleb / negative regulation of bone resorption / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / positive regulation of bone mineralization / response to ATP / protein homotrimerization / regulation of sodium ion transport / sodium channel activity / cellular response to ATP / positive regulation of NLRP3 inflammasome complex assembly / positive regulation of calcium ion transport into cytosol / The NLRP3 inflammasome / membrane depolarization / potassium channel activity / extrinsic apoptotic signaling pathway / Purinergic signaling in leishmaniasis infection / negative regulation of MAPK cascade / sensory perception of pain / response to ischemia / positive regulation of glycolytic process / apoptotic signaling pathway / positive regulation of interleukin-1 beta production / calcium-mediated signaling / neuromuscular junction / lipopolysaccharide binding / calcium ion transmembrane transport / cell-cell junction / cell surface receptor signaling pathway / postsynapse / external side of plasma membrane / signaling receptor binding / neuronal cell body / positive regulation of gene expression / GTP binding / ATP binding / membrane / metal ion binding / 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
ADENOSINE-5'-TRIPHOSPHATE / GUANOSINE-5'-DIPHOSPHATE / PALMITIC ACID / P2X purinoceptor 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.95 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

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


Theoretical massNumber of molelcules
Total (without water)215,76042
Polymers206,0153
Non-polymers9,74439
Water1,22568
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

-
Components

-
Protein / Sugars , 2 types, 15 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 / Production host: Homo sapiens (human) / References: UniProt: Q99572
#2: 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.: 12 / 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

-
Non-polymers , 5 types, 95 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
#5: Chemical
ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 15
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
#6: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 68 / Source method: isolated from a natural source / Formula: H2O

-
Details

Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

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

-
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

-
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: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 45 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 8721

-
Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 156509 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00713896
ELECTRON MICROSCOPYf_angle_d0.92118831
ELECTRON MICROSCOPYf_dihedral_angle_d14.3225151
ELECTRON MICROSCOPYf_chiral_restr0.0622037
ELECTRON MICROSCOPYf_plane_restr0.0052346

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more