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- EMDB-46781: Cryo-EM structure of the human P2X2 receptor in the apo closed state -

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Basic information

Entry
Database: EMDB / ID: EMD-46781
TitleCryo-EM structure of the human P2X2 receptor in the apo closed state
Map dataLocally sharpened map for hP2X2 in the apo closed state
Sample
  • Complex: Homotrimeric hP2X2
    • Protein or peptide: P2X purinoceptor 2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • 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: 2.71 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_46781.png

Downloads & links

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Map

FileDownload / File: emd_46781.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocally sharpened map for hP2X2 in the apo closed 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: 0.1
Minimum - Maximum-0.03291943 - 1.7812041
Average (Standard dev.)0.0006051737 (±0.015286366)
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_46781_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 the apo closed state

Fileemd_46781_additional_1.map
AnnotationUnsharpened map for hP2X2 in the apo closed 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 the apo closed state

Fileemd_46781_additional_2.map
AnnotationGlobally sharpened map for hP2X2 in the apo closed 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 the apo closed state

Fileemd_46781_half_map_1.map
AnnotationHalf map A for hP2X2 in the apo closed 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 the apo closed state

Fileemd_46781_half_map_2.map
AnnotationHalf map B for hP2X2 in the apo closed 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: 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: 51.814996 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAAQPKYPA GATARRLARG CWSALWDYET PKVIVVRNRR LGVLYRAVQL LILLYFVWYV FIVQKSYQES ETGPESSIIT KVKGITTSE HKVWDVEEYV KPPEGGSVFS IITRVEATHS QTQGTCPESI RVHNATCLSD ADCVAGELDM LGNGLRTGRC V PYYQGPSK ...String:
MAAAQPKYPA GATARRLARG CWSALWDYET PKVIVVRNRR LGVLYRAVQL LILLYFVWYV FIVQKSYQES ETGPESSIIT KVKGITTSE HKVWDVEEYV KPPEGGSVFS IITRVEATHS QTQGTCPESI RVHNATCLSD ADCVAGELDM LGNGLRTGRC V PYYQGPSK TCEVFGWCPV EDGASVSQFL GTMAPNFTIL IKNSIHYPKF HFSKGNIADR TDGYLKRCTF HEASDLYCPI FK LGFIVEK AGESFTELAH KGGVIGVIIN WDCDLDLPAS ECNPKYSFRR LDPKHVPASS GYNFRFAKYY KINGTTTRTL IKA YGIRID VIVHGQAGKF SLIPTIINLA TALTSVGVGS FLCDWILLTF MNKNKVYSHK KFDKVCTPSH PSGSWPVTLA RVLG QAPPE PGHRSEDQHP SPPSGQEGQQ GAECGPAFPP LRPCPISAPS EQMVDTPASE PAQASTPTDP KGLAQL

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: water

MacromoleculeName: water / type: ligand / ID: 3 / Number of copies: 180 / 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: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Number real images: 33324 / 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:

4dw0

Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.71 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 231214
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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