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- EMDB-39723: Cryo-EM structure of the panda P2X7 receptor in complex with PSFL1191 -

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Basic information

Entry
Database: EMDB / ID: EMD-39723
TitleCryo-EM structure of the panda P2X7 receptor in complex with PSFL1191
Map data
Sample
  • Complex: P2X7 trimer
    • Protein or peptide: P2X purinoceptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: PSFL1191
KeywordsChannel / TRANSPORT PROTEIN
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
Biological speciesAiluropoda melanoleuca (giant panda)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsSheng D / Hattori M
Funding support China, 1 items
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, 2024-
Header (metadata) releaseApr 16, 2025-
Map releaseApr 16, 2025-
UpdateMay 6, 2026-
Current statusMay 6, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_39723.png

Downloads & links

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Map

FileDownload / File: emd_39723.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.38
Minimum - Maximum-2.121855 - 2.381322
Average (Standard dev.)0.00020727808 (±0.06767345)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_39723_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_39723_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : P2X7 trimer

EntireName: P2X7 trimer
Components
  • Complex: P2X7 trimer
    • Protein or peptide: P2X purinoceptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: PSFL1191

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Supramolecule #1: P2X7 trimer

SupramoleculeName: P2X7 trimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Ailuropoda melanoleuca (giant panda)

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Macromolecule #1: P2X purinoceptor

MacromoleculeName: P2X purinoceptor / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Ailuropoda melanoleuca (giant panda)
Molecular weightTheoretical: 38.716234 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GSSTNYGTIK WIFHALVFSY ISFALISDKR YQKKEPLISS VHTKVKGIAE VKAEILENGM KKMVSGVFDT ADYTFPLQGN SFFVMTNFI KTEGQQQGLC PDFPTARTIC SSDRGCKKGR MDPQSKGIQT GRCVVYKERL KTCEVSAWCP IEEVKDAPRP A LLNSAENF ...String:
GSSTNYGTIK WIFHALVFSY ISFALISDKR YQKKEPLISS VHTKVKGIAE VKAEILENGM KKMVSGVFDT ADYTFPLQGN SFFVMTNFI KTEGQQQGLC PDFPTARTIC SSDRGCKKGR MDPQSKGIQT GRCVVYKERL KTCEVSAWCP IEEVKDAPRP A LLNSAENF TVLIKNNIDF PGHNYTTRNI LPGVNITCTF HKTQNPQCPI FRLGDIFQET GDSFSDVAIQ GGIMGIEIYW DC NLDGWFH HCRPKYSFRR LDDKTTSESL YPGYNFRYAK YYKENNVEKR TLIKVFGIRF DILVFGTGGK FNVIQLAVYI GSV ISYFGL ATVFIDILIN TYSASS

UniProtKB: P2X purinoceptor

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

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / 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 #3: PSFL1191

MacromoleculeName: PSFL1191 / type: ligand / ID: 3 / Number of copies: 3 / Formula: A1L0P
Molecular weightTheoretical: 379.449 Da

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 1.5 µm
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: OTHER / Details: CryoSPARC ab-initio reconstruction
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 161345
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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