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- EMDB-63466: Cryo-EM structure of the P2X1 receptor bound to ATP -

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Basic information

Entry
Database: EMDB / ID: EMD-63466
TitleCryo-EM structure of the P2X1 receptor bound to ATP
Map data
Sample
  • Complex: the ATP-bound P2X1 receptor
    • Protein or peptide: P2X purinoceptor 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: CHOLESTEROL
KeywordsIon channel / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of vascular associated smooth muscle contraction / 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 / serotonin secretion by platelet / ligand-gated calcium channel activity / Elevation of cytosolic Ca2+ levels ...regulation of vascular associated smooth muscle contraction / 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 / serotonin secretion by platelet / ligand-gated calcium channel activity / 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 / specific granule membrane / monoatomic cation channel activity / 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: 3.6 Å
AuthorsQiang Y / Chen K
Funding support China, 1 items
OrganizationGrant numberCountry
Chinese Academy of SciencesXDB37030100 China
CitationJournal: Acta Pharmacol Sin / Year: 2025
Title: Structural basis of the multiple ligand binding mechanisms of the P2X1 receptor.
Authors: Yu-Ting Qiang / Peng-Peng Wu / Xin Liu / Li Peng / Li-Ke Zhao / Ya-Ting Chen / Zhao-Bing Gao / Qiang Zhao / Kun Chen /
Abstract: As important modulators of human purinergic signaling, P2X1 receptors form homotrimers to transport calcium, regulating multiple physiological processes, and are long regarded as promising ...As important modulators of human purinergic signaling, P2X1 receptors form homotrimers to transport calcium, regulating multiple physiological processes, and are long regarded as promising therapeutic targets for male contraception and inflammation. However, the development of drugs that target the P2X1 receptor, such as the antagonist NF449, is greatly hindered by the unclear molecular mechanism of ligand binding modes and receptor activation. Here, we report the structures of the P2X1 receptor in complex with the endogenous agonist ATP or the competitive antagonist NF449. The P2X1 receptor displays distinct conformational features when bound to different types of compounds. Despite coupling to the agonist ATP, the receptor adopts a desensitized conformation that arrests the ions in the transmembrane (TM) domain, aligning with the nature of the high desensitization rates of the P2X1 receptor within the P2X family. Interestingly, the antagonist NF449 not only occupies the orthosteric pocket of ATP but also interacts with the dorsal fin, left flipper, and head domains, suggesting a unique binding mode to perform both orthosteric and allosteric mechanisms of NF449 inhibition. Intriguingly, a novel lipid binding site adjacent to the TM helices and lower body of P2X1, which is critical for receptor activation, is identified. Further functional assay results and structural alignments reveal the high conservation of this lipid binding site in P2X receptors, indicating important modulatory roles upon lipid binding. Taken together, these findings greatly increase our understanding of the ligand binding modes and multiple modulatory mechanisms of the P2X1 receptor and shed light on the further development of P2X1-selective antagonists.Keywords: Structural biology; Ligand binding mode; Ion channel; Purinergic P2X1 receptor.
History
DepositionFeb 17, 2025-
Header (metadata) releaseApr 16, 2025-
Map releaseApr 16, 2025-
UpdateApr 16, 2025-
Current statusApr 16, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63466.png

Downloads & links

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Map

FileDownload / File: emd_63466.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 274.176 Å		1.07 Å/pix.
x 256 pix.
= 274.176 Å		1.07 Å/pix.
x 256 pix.
= 274.176 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.071 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.13
Minimum - Maximum-1.153436 - 1.6663507
Average (Standard dev.)0.00050428056 (±0.030391768)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 274.176 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_63466_half_map_1.map
Projections & Slices
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Histogram (log scale)

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Half map: #2

Fileemd_63466_half_map_2.map
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Sample components

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Entire : the ATP-bound P2X1 receptor

EntireName: the ATP-bound P2X1 receptor
Components
  • Complex: the ATP-bound P2X1 receptor
    • Protein or peptide: P2X purinoceptor 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: CHOLESTEROL

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Supramolecule #1: the ATP-bound P2X1 receptor

SupramoleculeName: the ATP-bound P2X1 receptor / 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: 36.952723 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: KVGVIFRLIQ LVVLVYVIGW VFLYEKGYQT SSGLISSVSV KLKGLAVTQL PGLGPQVWDV ADYVFPAQGD NSFVVMTNFI VTPKQTQGY CAEHPEGGIC KEDSGCTPGK AKRKAQGIRT GKCVAFNDTV KTCEIFGWCP VEVDDDIPRP ALLREAENFT L FIKNSISF ...String:
KVGVIFRLIQ LVVLVYVIGW VFLYEKGYQT SSGLISSVSV KLKGLAVTQL PGLGPQVWDV ADYVFPAQGD NSFVVMTNFI VTPKQTQGY CAEHPEGGIC KEDSGCTPGK AKRKAQGIRT GKCVAFNDTV KTCEIFGWCP VEVDDDIPRP ALLREAENFT L FIKNSISF PRFKVNRRNL VEEVNAAHMK TCLFHKTLHP LCPVFQLGYV VQESGQNFST LAEKGGVVGI TIDWHCDLDW HV RHCRPIY EFHGLYEEKN LSPGFNFRFA RHFVENGTNY RHLFKVFGIR FDILVDGKAG KFDIIPTMTT IGSGIGIFGV ATV LCDLLL LHIL

UniProtKB: P2X purinoceptor 1

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Macromolecule #2: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / 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 #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 3 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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

Concentration7 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 346074
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-9lx5:
Cryo-EM structure of the P2X1 receptor bound to ATP

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