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- PDB-8z1d: Cryo-EM structure of the panda P2X7 receptor in complex with PSFL1191 -

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Basic information

Entry
Database: PDB / ID: 8z1d
TitleCryo-EM structure of the panda P2X7 receptor in complex with PSFL1191
ComponentsP2X purinoceptor
KeywordsTRANSPORT PROTEIN / Channel
Function / homology
Function and homology information


organophosphate ester transport / regulation of transport / positive regulation of cellular component organization / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / pore complex assembly / bleb assembly / response to ATP / membrane depolarization / positive regulation of interleukin-1 beta production ...organophosphate ester transport / regulation of transport / positive regulation of cellular component organization / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / pore complex assembly / bleb assembly / response to ATP / membrane depolarization / positive regulation of interleukin-1 beta production / calcium ion transmembrane transport / postsynapse / ATP 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
: / P2X purinoceptor
Similarity search - Component
Biological speciesAiluropoda melanoleuca (giant panda)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsSheng, D. / Hattori, M.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2025
Title: Understanding interspecies drug response variations between human and rodent P2X7 receptors.
Authors: Chang-Run Guo / Danqi Sheng / Ji-Yuan Li / Tian-Tian Li / Jia-Bao Yao / Rui Zhang / Ye Huang / Ying-Ying Zhao / Dong-Ping Wang / Jie Chen / Jian Li / Jiang Wang / Yu Zhou / Cheng Shen / Fei ...Authors: Chang-Run Guo / Danqi Sheng / Ji-Yuan Li / Tian-Tian Li / Jia-Bao Yao / Rui Zhang / Ye Huang / Ying-Ying Zhao / Dong-Ping Wang / Jie Chen / Jian Li / Jiang Wang / Yu Zhou / Cheng Shen / Fei Jin / Peng Cao / Motoyuki Hattori / Hong Liu / Ye Yu /
Abstract: Despite intensive development, P2X7 modulators have struggled in translation due to human genetic variability and species-dependent drug responses. Here, we identify PSFL1191, a portal-of-central- ...Despite intensive development, P2X7 modulators have struggled in translation due to human genetic variability and species-dependent drug responses. Here, we identify PSFL1191, a portal-of-central-pocket (PCP)-site inhibitor selective for human and panda P2X7, but inactive against rodents. Cryo-EM structures revealed two distinct PCP sub-pockets: PCP1, a rigid base pocket demanding precise steric complementarity with PSFL1191, and PCP2, a conserved middle cavity targeted by JNJ-54175446, a clinical candidate unaffected by species differences. Species selectivity maps to a deep PCP1 motif (V312-Y295-M105-F103-P96). In P2rx7 mice, PSFL1191 markedly altered macrophage-mediated bacterial clearance and wound healing while preserving basal physiology, effects absent in wild-type animals. Our findings establish the structural basis for interspecies pharmacological divergence in P2X7 modulation and highlight transgenic models as powerful tools for predicting therapeutic efficacy, thereby enabling more precise and efficient drug discovery.
History
DepositionApr 11, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 16, 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
B: P2X purinoceptor
C: P2X purinoceptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,61412
Polymers116,1493
Non-polymers2,4669
Water00
1


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

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Components

#1: Protein P2X purinoceptor


Mass: 38716.234 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Ailuropoda melanoleuca (giant panda) / Gene: PANDA_000894 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: D2GVW0
#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.: 6
Source method: isolated from a genetically manipulated source
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
#3: Chemical ChemComp-A1L0P / PSFL1191


Mass: 379.449 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C23H25NO4 / Feature type: SUBJECT OF INVESTIGATION
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: P2X7 trimer / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Ailuropoda melanoleuca (giant panda)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen 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 defocus max: 2300 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 161345 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0047659
ELECTRON MICROSCOPYf_angle_d0.67510413
ELECTRON MICROSCOPYf_dihedral_angle_d5.1281092
ELECTRON MICROSCOPYf_chiral_restr0.0481161
ELECTRON MICROSCOPYf_plane_restr0.0051320

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