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- EMDB-29945: Cryo-EM Structure of the Prostaglandin E2 Receptor 4 Coupled to G... -
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Open data
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Basic information
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Title | Cryo-EM Structure of the Prostaglandin E2 Receptor 4 Coupled to G Protein | |||||||||
![]() | PGE2-EP4-Gs-map | |||||||||
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![]() | GPCR complex / SIGNALING PROTEIN | |||||||||
Function / homology | ![]() negative regulation of eosinophil extravasation / prostaglandin E receptor activity / Prostanoid ligand receptors / negative regulation of integrin activation / response to nematode / T-helper cell differentiation / regulation of stress fiber assembly / negative regulation of cytokine production / PKA activation in glucagon signalling / hair follicle placode formation ...negative regulation of eosinophil extravasation / prostaglandin E receptor activity / Prostanoid ligand receptors / negative regulation of integrin activation / response to nematode / T-helper cell differentiation / regulation of stress fiber assembly / negative regulation of cytokine production / PKA activation in glucagon signalling / hair follicle placode formation / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / regulation of ossification / intracellular transport / D1 dopamine receptor binding / Hedgehog 'off' state / response to mechanical stimulus / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / JNK cascade / activation of adenylate cyclase activity / adenylate cyclase activator activity / ERK1 and ERK2 cascade / trans-Golgi network membrane / positive regulation of cytokine production / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / bone development / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / platelet aggregation / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / negative regulation of inflammatory response / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / positive regulation of inflammatory response / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / cellular response to mechanical stimulus / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / positive regulation of cytosolic calcium ion concentration / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / response to lipopolysaccharide / Extra-nuclear estrogen signaling / inflammatory response / immune response / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.1 Å | |||||||||
![]() | Shenming H / Mengyao X / Lei L / Jianqiang M / Jinpeng S | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 3.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 22 KB 22 KB | Display Display | ![]() |
Images | ![]() | 89.4 KB | ||
Filedesc metadata | ![]() | 7 KB | ||
Others | ![]() ![]() | 47.4 MB 1 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 585.6 KB | Display | ![]() |
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Full document | ![]() | 585.2 KB | Display | |
Data in XML | ![]() | 11.8 KB | Display | |
Data in CIF | ![]() | 13.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8gdbMC ![]() 8gcmC ![]() 8gcpC ![]() 8gd9C ![]() 8gdaC ![]() 8gdcC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
File | ![]() | ||||||||||||||||||||
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Annotation | PGE2-EP4-Gs-map | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.08 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: PGE2-EP4-Gs-map-half1
File | emd_29945_half_map_1.map | ||||||||||||
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Annotation | PGE2-EP4-Gs-map-half1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: PGE2-EP4-Gs-map-half2
File | emd_29945_half_map_2.map | ||||||||||||
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Annotation | PGE2-EP4-Gs-map-half2 | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Prostaglandin E Receptor EP4 Coupled to G Protein
Entire | Name: Prostaglandin E Receptor EP4 Coupled to G Protein |
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Components |
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-Supramolecule #1: Prostaglandin E Receptor EP4 Coupled to G Protein
Supramolecule | Name: Prostaglandin E Receptor EP4 Coupled to G Protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Macromolecule | Name: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 45.727441 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQD DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCA VDTENIRRVF NDCRDIIQRM HLRQYELL UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: 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 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 37.671102 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT ...String: PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DASAKLWDVR EGMCRQTFTG HESDINAICF FP NGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLLAGYDDFN CNVWDALKAD RAGVLAGHDN RVS CLGVTD DGMAVATGSW DSFLKIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #3: Guanine nucleotide-binding protein subunit gamma
Macromolecule | Name: Guanine nucleotide-binding protein subunit gamma / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 12.104898 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MWRELPLGLG ELHKDHQASR KLEPELWSVS ENPPSTSMAS NNTASIAQAR KLVEQLKMEA NIDRIKVSKA AADLMAYCEA HAKEDPLLT PVPASENPFR EKKFFCAIL UniProtKB: Guanine nucleotide-binding protein subunit gamma |
-Macromolecule #4: NB35
Macromolecule | Name: NB35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 13.885439 KDa |
Recombinant expression | Organism: unidentified (others) |
Sequence | String: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSS |
-Macromolecule #5: Prostaglandin E2 receptor EP4 subtype
Macromolecule | Name: Prostaglandin E2 receptor EP4 subtype / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 53.173336 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MSTPGVNSSA SLSPDRLNSP VTIPAVMFIF GVVGNLVAIV VLCKSRKEQK ETTFYTLVCG LAVTDLLGTL LVSPVTIATY MKGQWPGGQ PLCEYSTFIL LFFSLSGLSI ICAMSVERYL AINHAYFYSH YVDKRLAGLT LFAVYASNVL FCALPNMGLG S SRLQYPDT ...String: MSTPGVNSSA SLSPDRLNSP VTIPAVMFIF GVVGNLVAIV VLCKSRKEQK ETTFYTLVCG LAVTDLLGTL LVSPVTIATY MKGQWPGGQ PLCEYSTFIL LFFSLSGLSI ICAMSVERYL AINHAYFYSH YVDKRLAGLT LFAVYASNVL FCALPNMGLG S SRLQYPDT WCFIDWTTNV TAHAAYSYMY AGFSSFLILA TVLCNVLVCG ALLRMHRQFM RRTSLGTEQH HAAAAASVAS RG HPAASPA LPRLSDFRRR RSFRRIAGAE IQMVILLIAT SLVVLICSIP LVVRVFVNQL YQPSLEREVS KNPDLQAIRI ASV NPILDP WIYILLRKTV LSKAIEKIKC LFCRIGGSRR ERSGQHCSDS QRTSSAMSGH SRSFISRELK EISSTSQTLL PDLS LPDLS ENGLGGRNLL PGVPGMGLAQ EDTTSLRTLR ISETSDSSQG QDSESVLLVD EAGGSGRAGP APKGSSLQVT FPSET LNLS EKCI UniProtKB: Prostaglandin E2 receptor EP4 subtype |
-Macromolecule #6: (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxo-...
Macromolecule | Name: (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxo-cyclopentyl]hept-5-enoic acid type: ligand / ID: 6 / Number of copies: 1 / Formula: P2E |
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Molecular weight | Theoretical: 352.465 Da |
Chemical component information | ![]() ChemComp-P2E: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 25.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: OTHER |
Electron optics | Illumination 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 model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 258283 |
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: PROJECTION MATCHING |