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- EMDB-46783: Cryo-EM structure of the human P2X2 receptor in conformation II o... -

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Basic information

Entry
Database: EMDB / ID: EMD-46783
TitleCryo-EM structure of the human P2X2 receptor in conformation II of the ATP-bound desensitized state
Map dataLocally sharpened map for hP2X2 in conformation II of the ATP-bound desensitized state
Sample
  • Complex: Homotrimeric hP2X2
    • Protein or peptide: P2X purinoceptor 2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: water
KeywordsMembrane Protein / Ion Channel / Ligand-gated Ion Channel / P2X Receptor / P2XR
Function / homology
Function and homology information


detection of hypoxic conditions in blood by carotid body chemoreceptor signaling / Platelet homeostasis / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / peristalsis / Elevation of cytosolic Ca2+ levels / neuromuscular synaptic transmission / urinary bladder smooth muscle contraction / response to carbohydrate / ligand-gated monoatomic ion channel activity ...detection of hypoxic conditions in blood by carotid body chemoreceptor signaling / Platelet homeostasis / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / peristalsis / Elevation of cytosolic Ca2+ levels / neuromuscular synaptic transmission / urinary bladder smooth muscle contraction / response to carbohydrate / ligand-gated monoatomic ion channel activity / response to ATP / neuromuscular junction development / behavioral response to pain / positive regulation of calcium ion transport into cytosol / neuronal dense core vesicle / skeletal muscle fiber development / positive regulation of calcium-mediated signaling / response to ischemia / sensory perception of sound / calcium ion transmembrane transport / sensory perception of taste / response to hypoxia / receptor complex / postsynapse / apical plasma membrane / neuronal cell body / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
P2X2 purinoceptor / : / ATP P2X receptors signature. / ATP P2X receptor / P2X purinoreceptor / P2X purinoreceptor extracellular domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.55 Å
AuthorsWestermann FG / Oken AC / Muller CE / Mansoor SE
Funding support United States, 2 items
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: Proc Natl Acad Sci U S A / Year: 2025
Title: Subtype-specific structural features of the hearing loss-associated human P2X2 receptor.
Authors: Franka G Westermann / Adam C Oken / Philip K E Granith / Parthiban Marimuthu / Christa E Müller / Steven E Mansoor /
Abstract: The P2X2 receptor (P2X2R) is a slowly desensitizing adenosine triphosphate (ATP)-gated ion channel that is highly expressed in the cochlea. When mutated, the P2X2R exacerbates age- and noise-related ...The P2X2 receptor (P2X2R) is a slowly desensitizing adenosine triphosphate (ATP)-gated ion channel that is highly expressed in the cochlea. When mutated, the P2X2R exacerbates age- and noise-related hearing loss, but selective modulators of the receptor are lacking, and the molecular basis of activation and desensitization remains poorly understood. Here, we determine high-resolution cryoelectron microscopy structures of the full-length wild-type human P2X2R in an apo closed state and two distinct ATP-bound desensitized states. In the apo closed state structure, we observe features unique to the P2X2R and locate disease mutations within or near the transmembrane domain. In addition, our ATP-bound structures show how free anionic ATP forms subtype-specific interactions with the orthosteric binding site. We identify and characterize two different ATP-bound desensitized state structures, one similar to published models for other P2XR subtypes, and a second alternate conformation not previously observed. A loop adjacent to the orthosteric binding site between these two ATP-bound desensitized state structures undergoes significant conformational changes. These movements are supported by multireplicate, microsecond-scale molecular dynamics simulation studies and suggest a path by which ATP could enter or leave the orthosteric pocket. Together, our results provide structural insights into the P2X2R, facilitating structure-based drug development for this therapeutically important target.
History
DepositionAug 28, 2024-
Header (metadata) releaseSep 24, 2025-
Map releaseSep 24, 2025-
UpdateSep 24, 2025-
Current statusSep 24, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46783.png

Downloads & links

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Map

FileDownload / File: emd_46783.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocally sharpened map for hP2X2 in conformation II of the ATP-bound desensitized state
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 500 pix.
= 324. Å		0.65 Å/pix.
x 500 pix.
= 324. Å		0.65 Å/pix.
x 500 pix.
= 324. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.648 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.04205181 - 1.477779
Average (Standard dev.)0.00054301776 (±0.014112733)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions500500500
Spacing500500500
CellA=B=C: 324.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_46783_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened map for hP2X2 in conformation II of...

Fileemd_46783_additional_1.map
AnnotationUnsharpened map for hP2X2 in conformation II of the ATP-bound desensitized state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Globally sharpened map for hP2X2 in conformation II...

Fileemd_46783_additional_2.map
AnnotationGlobally sharpened map for hP2X2 in conformation II of the ATP-bound desensitized state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B for hP2X2 in conformation II...

Fileemd_46783_half_map_1.map
AnnotationHalf map B for hP2X2 in conformation II of the ATP-bound desensitized state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A for hP2X2 in conformation II...

Fileemd_46783_half_map_2.map
AnnotationHalf map A for hP2X2 in conformation II of the ATP-bound desensitized state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Homotrimeric hP2X2

EntireName: Homotrimeric hP2X2
Components
  • Complex: Homotrimeric hP2X2
    • Protein or peptide: P2X purinoceptor 2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: water

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Supramolecule #1: Homotrimeric hP2X2

SupramoleculeName: Homotrimeric hP2X2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: P2X purinoceptor 2

MacromoleculeName: P2X purinoceptor 2 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 35.453492 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: VLYRAVQLLI LLYFVWYVFI VQKSYQESET GPESSIITKV KGITTSEHKV WDVEEYVKPP EGGSVFSIIT RVEATHSQTQ GTCPESIRV HNATCLSDAD CVAGELDMLG NGLRTGRCVP YYQGPSKTCE VFGWCPVEDG ASVSQFLGTM APNFTILIKN S IHYPKFHF ...String:
VLYRAVQLLI LLYFVWYVFI VQKSYQESET GPESSIITKV KGITTSEHKV WDVEEYVKPP EGGSVFSIIT RVEATHSQTQ GTCPESIRV HNATCLSDAD CVAGELDMLG NGLRTGRCVP YYQGPSKTCE VFGWCPVEDG ASVSQFLGTM APNFTILIKN S IHYPKFHF SKGNIADRTD GYLKRCTFHE ASDLYCPIFK LGFIVEKAGE SFTELAHKGG VIGVIINWDC DLDLPASECN PK YSFRRLD PKHVPASSGY NFRFAKYYKI NGTTTRTLIK AYGIRIDVIV HGQAGKFSLI PTIINLATAL TSVGVGSFLC DW

UniProtKB: P2X purinoceptor 2

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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: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 3 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 147 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Slit width: 10 eV
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Number real images: 27324 / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated magnification: 130000 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.9 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
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: PDB ENTRY
PDB model - PDB ID:

5svl

Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.55 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 108423
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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