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- EMDB-63571: Cryo-EM structure of PGE2-EP1-Gq complex -

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Entry
Database: EMDB / ID: EMD-63571
TitleCryo-EM structure of PGE2-EP1-Gq complex
Map data
Sample
  • Complex: PGE2-EP1-Gq complex
    • Protein or peptide: Prostaglandin E2 receptor EP1 subtype
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Ligand: (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxo-cyclopentyl]hept-5-enoic acid
  • Ligand: water
KeywordsGPCR / EP1 / PGE2 / Gq / MEMBRANE PROTEIN
Function / homology
Function and homology information


prostaglandin E receptor activity / Prostanoid ligand receptors / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / regulation of platelet activation / entrainment of circadian clock / regulation of canonical Wnt signaling pathway ...prostaglandin E receptor activity / Prostanoid ligand receptors / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / regulation of platelet activation / entrainment of circadian clock / regulation of canonical Wnt signaling pathway / glutamate receptor signaling pathway / phototransduction, visible light / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / photoreceptor outer segment / D1 dopamine receptor binding / intracellular transport / neuropeptide signaling pathway / postsynaptic cytosol / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / adenylate cyclase inhibitor activity / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of protein localization to cell cortex / enzyme regulator activity / T cell migration / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / response to prostaglandin E / adenylate cyclase regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of insulin secretion / cellular response to glucagon stimulus / cellular response to forskolin / GTPase activator activity / regulation of mitotic spindle organization / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / adenylate cyclase activator activity / trans-Golgi network membrane / Regulation of insulin secretion / negative regulation of inflammatory response to antigenic stimulus / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / response to peptide hormone / bone development / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / platelet aggregation / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / cognition / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / blood coagulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / GDP binding / sensory perception of smell / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of taste / positive regulation of cold-induced thermogenesis / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / positive regulation of cytosolic calcium ion concentration
Similarity search - Function
Prostanoid EP1 receptor / Prostaglandin DP receptor / Prostanoid receptor / G-protein alpha subunit, group Q / G-protein alpha subunit, group S / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. ...Prostanoid EP1 receptor / Prostaglandin DP receptor / Prostanoid receptor / G-protein alpha subunit, group Q / G-protein alpha subunit, group S / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Prostaglandin E2 receptor EP1 subtype / Guanine nucleotide-binding protein G(q) subunit alpha / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.55 Å
AuthorsMeng X / Xu Y / Xu HE
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81902085 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Structural insights into the activation of the human prostaglandin E receptor EP1 subtype by prostaglandin E.
Authors: Xue Meng / Yang Li / Jiuyin Xu / Kai Wu / Wen Hu / Canrong Wu / H Eric Xu / Youwei Xu /
Abstract: Prostaglandin E (PGE) mediates diverse physiological processes through four G protein-coupled receptor subtypes (EP1-EP4). While structures of EP2, EP3, and EP4 have been determined, the structural ...Prostaglandin E (PGE) mediates diverse physiological processes through four G protein-coupled receptor subtypes (EP1-EP4). While structures of EP2, EP3, and EP4 have been determined, the structural basis for PGE recognition and activation of the EP1 receptor subtype has remained elusive due to its inherent instability. Here, we present the cryoelectron microscopy structure of the human EP1 receptor in complex with PGE and heterotrimeric Gq protein at 2.55 Å resolution, completing the structural characterization of the EP receptor family. Our structure reveals a unique binding mode of PGE within EP1, involving key interactions with residues in the orthosteric pocket. Notably, we observe a less pronounced outward displacement of transmembrane helix 6 compared to other EP receptor subtypes, suggesting a distinct activation mechanism for EP1. Through extensive mutational analyses, we identify critical residues involved in PGE recognition, EP1 activation, and Gq protein coupling. By overcoming the challenges associated with the instability of EP1, our findings provide valuable insights into the subtype-specific activation mechanisms of EP receptors and lay the foundation for the development of more selective EP1-targeted therapeutics.
History
DepositionFeb 26, 2025-
Header (metadata) releaseApr 30, 2025-
Map releaseApr 30, 2025-
UpdateNov 12, 2025-
Current statusNov 12, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63571.png

Downloads & links

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Map

FileDownload / File: emd_63571.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 320 pix.
= 263.68 Å		0.82 Å/pix.
x 320 pix.
= 263.68 Å		0.82 Å/pix.
x 320 pix.
= 263.68 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.354
Minimum - Maximum-2.4388397 - 4.689018
Average (Standard dev.)-0.0012597302 (±0.07051968)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 263.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_63571_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_63571_half_map_2.map
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Sample components

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Entire : PGE2-EP1-Gq complex

EntireName: PGE2-EP1-Gq complex
Components
  • Complex: PGE2-EP1-Gq complex
    • Protein or peptide: Prostaglandin E2 receptor EP1 subtype
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Ligand: (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxo-cyclopentyl]hept-5-enoic acid
  • Ligand: water

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Supramolecule #1: PGE2-EP1-Gq complex

SupramoleculeName: PGE2-EP1-Gq complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Prostaglandin E2 receptor EP1 subtype

MacromoleculeName: Prostaglandin E2 receptor EP1 subtype / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.84723 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MSPCGPLNLS LAGEATTCAA PWVPNTSAVP PSGASPALPI FSMTLGAVSN LLALALLAQA AGRLRRRRSA ATFLLFVASL LATDLAGHV IPGALVLRLY TAGRAPAGGA CHFLGGCMVF FGLCPLLLGC GMAVERCVGV TRPLLHAARV SVARARLALA A VAAVALAV ...String:
MSPCGPLNLS LAGEATTCAA PWVPNTSAVP PSGASPALPI FSMTLGAVSN LLALALLAQA AGRLRRRRSA ATFLLFVASL LATDLAGHV IPGALVLRLY TAGRAPAGGA CHFLGGCMVF FGLCPLLLGC GMAVERCVGV TRPLLHAARV SVARARLALA A VAAVALAV ALLPLARVGR YELQYPGTWC FIGLGPPGGW RQALLAGLFA SLGLVALLAA LVCNTLSGLA LLRARWRRRS RR PPPASGP DSRRRWGAHG PRSASASSAS SIASASTFFG GSRSSGSARR ARAHDVEMVG QLVGIMVVSC ICWSPMLVLV ALA VGGWSS TSLQRPLFLA VRLASWNQIL DPWVYILLRQ AVLRQLLRLL PPRAGAKGGP AGLGLTPSAW EASSLRSSRH SGLS HF

UniProtKB: Prostaglandin E2 receptor EP1 subtype

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Macromolecule #2: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine n...

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.724383 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RRTLRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RRTLRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTSGIFETK FQVDKVNFHM FDVGAQRDER RKWIQCFNDV TAIIFVVDSS DYNRLQEALN DF KSIWNNR WLRTISVILF LNKQDLLAEK VLAGKSKIED YFPEFARYTT PEDATPEPGE DPRVTRAKYF IRKEFVDIST ASG DGRHIC YPHFTCSVDT ENARRIFNDC KDIILQMNLR EYNLV

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(i) subunit alpha-1, ...UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(q) subunit alpha

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.915496 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String:
MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #5: (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxo-...

MacromoleculeName: (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxo-cyclopentyl]hept-5-enoic acid
type: ligand / ID: 5 / Number of copies: 1 / Formula: P2E
Molecular weightTheoretical: 352.465 Da
Chemical component information

ChemComp-P2E:
(Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxo-cyclopentyl]hept-5-enoic acid / medication*YM

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 1 / 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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.55 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 543885
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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