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- EMDB-29946: Cryo-EM Structure of the Prostaglandin E2 Receptor 3 Coupled to G... -

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Entry
Database: EMDB / ID: EMD-29946
TitleCryo-EM Structure of the Prostaglandin E2 Receptor 3 Coupled to G Protein
Map dataPGE2-EP3-Gi-map
Sample
  • Complex: Prostaglandin E Receptor EP4 Coupled to G Protein
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein subunit gamma
    • Protein or peptide: Prostaglandin E2 receptor EP3 subtype
  • Ligand: (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxo-cyclopentyl]hept-5-enoic acid
KeywordsGPCR complex / SIGNALING PROTEIN
Function / homology
Function and homology information


negative regulation of gastric acid secretion / intestine smooth muscle contraction / prostaglandin E receptor activity / Prostanoid ligand receptors / cell death / positive regulation of fever generation / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding ...negative regulation of gastric acid secretion / intestine smooth muscle contraction / prostaglandin E receptor activity / Prostanoid ligand receptors / cell death / positive regulation of fever generation / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / regulation of mitotic spindle organization / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / G-protein beta/gamma-subunit complex binding / centriolar satellite / Olfactory 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / nuclear envelope / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / G protein activity / GTPase binding / positive regulation of cytosolic calcium ion concentration / Ca2+ pathway / retina development in camera-type eye / midbody / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body / G protein-coupled receptor signaling pathway / inflammatory response / lysosomal membrane / cell division / GTPase activity / synapse / centrosome / protein-containing complex binding / GTP binding / nucleolus / magnesium ion binding / Golgi apparatus / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol
Similarity search - Function
Prostanoid EP3 receptor / Prostanoid EP3 receptor, type 2 / Prostaglandin DP receptor / Prostanoid receptor / 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 ...Prostanoid EP3 receptor / Prostanoid EP3 receptor, type 2 / Prostaglandin DP receptor / Prostanoid receptor / 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 / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / 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
Guanine nucleotide-binding protein subunit gamma / Prostaglandin E2 receptor EP3 subtype / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsShenming H / Mengyao X / Lei L / Yang D / Shiyi G / Jinpeng S
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81825022 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: Single hormone or synthetic agonist induces G/G coupling selectivity of EP receptors via distinct binding modes and propagating paths.
Authors: Shen-Ming Huang / Meng-Yao Xiong / Lei Liu / Jianqiang Mu / Ming-Wei Wang / Ying-Li Jia / Kui Cai / Lu Tie / Chao Zhang / Sheng Cao / Xin Wen / Jia-Le Wang / Sheng-Chao Guo / Yu Li / Chang- ...Authors: Shen-Ming Huang / Meng-Yao Xiong / Lei Liu / Jianqiang Mu / Ming-Wei Wang / Ying-Li Jia / Kui Cai / Lu Tie / Chao Zhang / Sheng Cao / Xin Wen / Jia-Le Wang / Sheng-Chao Guo / Yu Li / Chang-Xiu Qu / Qing-Tao He / Bo-Yang Cai / Chenyang Xue / Shiyi Gan / Yihe Xie / Xin Cong / Zhao Yang / Wei Kong / Shuo Li / Zijian Li / Peng Xiao / Fan Yang / Xiao Yu / You-Fei Guan / Xiaoyan Zhang / Zhongmin Liu / Bao-Xue Yang / Yang Du / Jin-Peng Sun /
Abstract: To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) ...To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, , re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, , 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, , 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that G-biased signaling, but not G activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-G, EP4-G, and EP4-G in complex with endogenous prostaglandin E (PGE)or two synthetic agonists and comparing with PGE-EP2-G structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the G/G transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their G/G coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for G/G coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.
History
DepositionMar 3, 2023-
Header (metadata) releaseJan 10, 2024-
Map releaseJan 10, 2024-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29946.png

Downloads & links

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Map

FileDownload / File: emd_29946.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPGE2-EP3-Gi-map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 200 pix.
= 170. Å		0.85 Å/pix.
x 200 pix.
= 170. Å		0.85 Å/pix.
x 200 pix.
= 170. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.025
Minimum - Maximum-0.028283117 - 2.0383716
Average (Standard dev.)0.0021200604 (±0.030466054)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 170.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_29946_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: PGE2-EP3-Gi-map-half1

Fileemd_29946_half_map_1.map
AnnotationPGE2-EP3-Gi-map-half1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: PGE2-EP3-Gi-map-half2

Fileemd_29946_half_map_2.map
AnnotationPGE2-EP3-Gi-map-half2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Prostaglandin E Receptor EP4 Coupled to G Protein

EntireName: Prostaglandin E Receptor EP4 Coupled to G Protein
Components
  • Complex: Prostaglandin E Receptor EP4 Coupled to G Protein
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein subunit gamma
    • Protein or peptide: Prostaglandin E2 receptor EP3 subtype
  • Ligand: (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxo-cyclopentyl]hept-5-enoic acid

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Supramolecule #1: Prostaglandin E Receptor EP4 Coupled to G Protein

SupramoleculeName: Prostaglandin E Receptor EP4 Coupled to G Protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.445059 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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Macromolecule #2: 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: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.418086 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR ...String:
MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR FLDDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TF TGHESDI NAICFFPNGN AFATGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKA DRAGVL AGHDNRVSCL GVTDDGMAVA TGSWDSFLKI WN

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

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Macromolecule #3: Guanine nucleotide-binding protein subunit gamma

MacromoleculeName: Guanine nucleotide-binding protein subunit gamma / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.104898 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString:
MWRELPLGLG ELHKDHQASR KLEPELWSVS ENPPSTSMAS NNTASIAQAR KLVEQLKMEA NIDRIKVSKA AADLMAYCEA HAKEDPLLT PVPASENPFR EKKFFCAIL

UniProtKB: Guanine nucleotide-binding protein subunit gamma

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Macromolecule #4: Prostaglandin E2 receptor EP3 subtype

MacromoleculeName: Prostaglandin E2 receptor EP3 subtype / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.357711 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: MKETRGYGGD APFCTRLNHS YTGMWAPERS AEARGNLTRP PGSGEDCGSV SVAFPITMLL TGFVGNALAM LLVSRSYRRR ESKRKKSFL LCIGWLALTD LVGQLLTTPV VIVVYLSKQR WEHIDPSGRL CTFFGLTMTV FGLSSLFIAS AMAVERALAI R APHWYASH ...String:
MKETRGYGGD APFCTRLNHS YTGMWAPERS AEARGNLTRP PGSGEDCGSV SVAFPITMLL TGFVGNALAM LLVSRSYRRR ESKRKKSFL LCIGWLALTD LVGQLLTTPV VIVVYLSKQR WEHIDPSGRL CTFFGLTMTV FGLSSLFIAS AMAVERALAI R APHWYASH MKTRATRAVL LGVWLAVLAF ALLPVLGVGQ YTVQWPGTWC FISTGRGGNG TSSSHNWGNL FFASAFAFLG LL ALTVTFS CNLATIKALV SRCRAKATAS QSSAQWGRIT TETAIQLMGI MCVLSVCWSP LLIMMLKMIF NQTSVEHCKT HTE KQKECN FFLIAVRLAS LNQILDPWVY LLLRKILLRK FCQIRYHTNN YASSSTSLPC QCSSTLMWSD HLER

UniProtKB: Prostaglandin E2 receptor EP3 subtype

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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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 25.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: OTHER
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.0 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: PDB ENTRY
PDB model - PDB ID:

7cx2

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 625888
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: PROJECTION MATCHING

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