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- EMDB-45152: Cryo-EM structure of the human P2X1 receptor in the apo closed state -

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Basic information

Entry
Database: EMDB / ID: EMD-45152
TitleCryo-EM structure of the human P2X1 receptor in the apo closed state
Map dataDeepEMhancer sharpened map for hP2X1 in the apo closed state
Sample
  • Complex: Membrane protein
    • Protein or peptide: P2X purinoceptor 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: water
KeywordsMembrane Protein / Ion Channel / Ligand-gated Ion Channel / P2X Receptor / Allosteric Antagonist
Function / homology
Function and homology information


Platelet homeostasis / insemination / positive regulation of calcium ion import across plasma membrane / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / suramin binding / regulation of vascular associated smooth muscle contraction / ligand-gated calcium channel activity / serotonin secretion by platelet / Elevation of cytosolic Ca2+ levels ...Platelet homeostasis / insemination / positive regulation of calcium ion import across plasma membrane / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / suramin binding / regulation of vascular associated smooth muscle contraction / ligand-gated calcium channel activity / serotonin secretion by platelet / Elevation of cytosolic Ca2+ levels / regulation of presynaptic cytosolic calcium ion concentration / ceramide biosynthetic process / response to ATP / regulation of synaptic vesicle exocytosis / neuronal action potential / monoatomic cation channel activity / specific granule membrane / monoatomic ion transport / presynaptic active zone membrane / secretory granule membrane / synaptic transmission, glutamatergic / calcium ion transmembrane transport / platelet activation / regulation of blood pressure / postsynaptic membrane / membrane raft / external side of plasma membrane / apoptotic process / Neutrophil degranulation / protein-containing complex binding / glutamatergic synapse / signal transduction / protein-containing complex / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
P2X1 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: 2.74 Å
AuthorsOken AC / Lisi NE / Ditter IA / Shi H / 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: Nat Commun / Year: 2024
Title: Cryo-EM structures of the human P2X1 receptor reveal subtype-specific architecture and antagonism by supramolecular ligand-binding.
Authors: Adam C Oken / Nicolas E Lisi / Ismayn A Ditter / Haoyuan Shi / Nadia A Nechiporuk / Steven E Mansoor /
Abstract: P2X receptors are a family of seven trimeric non-selective cation channels that are activated by extracellular ATP to play roles in the cardiovascular, neuronal, and immune systems. Although it is ...P2X receptors are a family of seven trimeric non-selective cation channels that are activated by extracellular ATP to play roles in the cardiovascular, neuronal, and immune systems. Although it is known that the P2X1 receptor subtype has increased sensitivity to ATP and fast desensitization kinetics, an underlying molecular explanation for these subtype-selective features is lacking. Here we report high-resolution cryo-EM structures of the human P2X1 receptor in the apo closed, ATP-bound desensitized, and the high-affinity antagonist NF449-bound inhibited states. The apo closed and ATP-bound desensitized state structures of human P2X1 define subtype-specific properties such as distinct pore architecture and ATP-interacting residues. The NF449-bound inhibited state structure of human P2X1 reveals that NF449 has a unique dual-ligand supramolecular binding mode at the interface of neighboring protomers, inhibiting channel activation by overlapping with the canonical P2X receptor ATP-binding site. Altogether, these data define the molecular pharmacology of the human P2X1 receptor laying the foundation for structure-based drug design.
History
DepositionMay 30, 2024-
Header (metadata) releaseOct 9, 2024-
Map releaseOct 9, 2024-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45152.png

Downloads & links

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Map

FileDownload / File: emd_45152.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDeepEMhancer sharpened map for hP2X1 in the apo closed state
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 400 pix.
= 259.52 Å		0.65 Å/pix.
x 400 pix.
= 259.52 Å		0.65 Å/pix.
x 400 pix.
= 259.52 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.6488 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.040339977 - 1.664192
Average (Standard dev.)0.001024252 (±0.01996815)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 259.52002 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_45152_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 hP2X1 in the apo closed state

Fileemd_45152_additional_1.map
AnnotationUnsharpened map for hP2X1 in the apo closed state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Sharpened map for hP2X1 in the apo closed state

Fileemd_45152_additional_2.map
AnnotationSharpened map for hP2X1 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 hP2X1 in the apo closed state

Fileemd_45152_half_map_1.map
AnnotationHalf map B for hP2X1 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 hP2X1 in the apo closed state

Fileemd_45152_half_map_2.map
AnnotationHalf map A for hP2X1 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 : Membrane protein

EntireName: Membrane protein
Components
  • Complex: Membrane protein
    • Protein or peptide: P2X purinoceptor 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: water

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Supramolecule #1: Membrane protein

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

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Macromolecule #1: P2X purinoceptor 1

MacromoleculeName: P2X purinoceptor 1 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.038957 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MARRFQEELA AFLFEYDTPR MVLVRNKKVG VIFRLIQLVV LVYVIGWVFL YEKGYQTSSG LISSVSVKLK GLAVTQLPGL GPQVWDVAD YVFPAQGDNS FVVMTNFIVT PKQTQGYCAE HPEGGICKED SGCTPGKAKR KAQGIRTGKC VAFNDTVKTC E IFGWCPVE ...String:
MARRFQEELA AFLFEYDTPR MVLVRNKKVG VIFRLIQLVV LVYVIGWVFL YEKGYQTSSG LISSVSVKLK GLAVTQLPGL GPQVWDVAD YVFPAQGDNS FVVMTNFIVT PKQTQGYCAE HPEGGICKED SGCTPGKAKR KAQGIRTGKC VAFNDTVKTC E IFGWCPVE VDDDIPRPAL LREAENFTLF IKNSISFPRF KVNRRNLVEE VNAAHMKTCL FHKTLHPLCP VFQLGYVVQE SG QNFSTLA EKGGVVGITI DWHCDLDWHV RHCRPIYEFH GLYEEKNLSP GFNFRFARHF VENGTNYRHL FKVFGIRFDI LVD GKAGKF DIIPTMTTIG SGIGIFGVAT VLCDLLLLHI LPKRHYYKQK KFKYAEDMGP GAAERDLAAT SSTLGLQENM RTS

UniProtKB: P2X purinoceptor 1

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 9 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #4: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 4 / Number of copies: 6 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 102 / 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 (6k x 4k) / Number real images: 13512 / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 130000
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:

5svj

Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 205977
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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