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- EMDB-34663: Cryo-EM structure of endothelin1-bound ETAR-Gq complex -

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Entry
Database: EMDB / ID: EMD-34663
TitleCryo-EM structure of endothelin1-bound ETAR-Gq complex
Map data
Sample
  • Complex: ET1-ETAR-Gq-scFv16 complex
    • Protein or peptide: Endothelin-1 receptor,Oplophorus-luciferin 2-monooxygenase catalytic subunit chimera
    • Protein or peptide: Endothelin-1Endothelin 1
    • Protein or peptide: Guanine nucleotide-binding protein G(q) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: scFv16
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
KeywordsET1 / ETAR / Gq / scFv16 / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of protein localization to cell leading edge / : / endothelin receptor activity / positive regulation of prostaglandin-endoperoxide synthase activity / endothelin A receptor binding / protein kinase C deactivation / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / phospholipase D-activating G protein-coupled receptor signaling pathway / endothelin B receptor binding ...regulation of protein localization to cell leading edge / : / endothelin receptor activity / positive regulation of prostaglandin-endoperoxide synthase activity / endothelin A receptor binding / protein kinase C deactivation / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / phospholipase D-activating G protein-coupled receptor signaling pathway / endothelin B receptor binding / rhythmic excitation / peptide hormone secretion / neural crest cell fate commitment / sympathetic neuron axon guidance / Oplophorus-luciferin 2-monooxygenase / body fluid secretion / Oplophorus-luciferin 2-monooxygenase activity / glomerular endothelium development / vein smooth muscle contraction / noradrenergic neuron differentiation / response to prostaglandin F / positive regulation of renal sodium excretion / leukocyte activation / positive regulation of sarcomere organization / vascular associated smooth muscle cell development / atrial cardiac muscle tissue development / histamine secretion / heparin metabolic process / rough endoplasmic reticulum lumen / positive regulation of chemokine-mediated signaling pathway / positive regulation of odontogenesis / maternal process involved in parturition / cardiac chamber formation / pharyngeal arch artery morphogenesis / regulation of glucose transmembrane transport / endothelin receptor signaling pathway involved in heart process / semaphorin-plexin signaling pathway involved in axon guidance / epithelial fluid transport / podocyte differentiation / cardiac neural crest cell migration involved in outflow tract morphogenesis / negative regulation of hormone secretion / protein transmembrane transport / response to leptin / endothelin receptor signaling pathway / response to ozone / sodium ion homeostasis / Weibel-Palade body / developmental pigmentation / response to acetylcholine / renal sodium ion absorption / positive regulation of cell growth involved in cardiac muscle cell development / mesenchymal cell apoptotic process / glomerular filtration / artery smooth muscle contraction / podocyte apoptotic process / left ventricular cardiac muscle tissue morphogenesis / embryonic skeletal system development / axonogenesis involved in innervation / enteric nervous system development / positive regulation of cation channel activity / positive regulation of prostaglandin secretion / renal albumin absorption / cellular response to follicle-stimulating hormone stimulus / cellular response to luteinizing hormone stimulus / cranial skeletal system development / regulation of pH / negative regulation of nitric-oxide synthase biosynthetic process / cellular response to mineralocorticoid stimulus / positive regulation of urine volume / respiratory gaseous exchange by respiratory system / basal part of cell / positive regulation of smooth muscle contraction / sympathetic nervous system development / phosphatidylinositol phospholipase C activity / norepinephrine metabolic process / positive regulation of hormone secretion / regulation of systemic arterial blood pressure by endothelin / vasoconstriction / protein kinase C-activating G protein-coupled receptor signaling pathway / embryonic heart tube development / negative regulation of blood coagulation / axon extension / superoxide anion generation / dorsal/ventral pattern formation / establishment of endothelial barrier / positive regulation of neutrophil chemotaxis / middle ear morphogenesis / positive regulation of signaling receptor activity / cellular response to glucocorticoid stimulus / cartilage development / aorta development / prostaglandin biosynthetic process / neuromuscular process / negative regulation of protein metabolic process / nitric oxide transport / cellular response to fatty acid / neuron remodeling / cellular response to organic substance / branching involved in blood vessel morphogenesis / positive regulation of heart rate
Similarity search - Function
Endothelin receptor A / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / Endothelin family / Endothelin family signature. / Endothelin / Calycin / G-protein, gamma subunit ...Endothelin receptor A / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / Endothelin family / Endothelin family signature. / Endothelin / Calycin / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 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 / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Endothelin-1 / Endothelin-1 receptor / 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 / Oplophorus-luciferin 2-monooxygenase catalytic subunit
Similarity search - Component
Biological speciesHomo (humans) / Homo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsYuan Q / Jiang Y / Xu HE / Ji Y / Duan J
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis of peptide recognition and activation of endothelin receptors.
Authors: Yujie Ji / Jia Duan / Qingning Yuan / Xinheng He / Gong Yang / Shengnan Zhu / Kai Wu / Wen Hu / Tianyu Gao / Xi Cheng / Hualiang Jiang / H Eric Xu / Yi Jiang /
Abstract: Endothelin system comprises three endogenous 21-amino-acid peptide ligands endothelin-1, -2, and -3 (ET-1/2/3), and two G protein-coupled receptor (GPCR) subtypes-endothelin receptor A (ETR) and B ...Endothelin system comprises three endogenous 21-amino-acid peptide ligands endothelin-1, -2, and -3 (ET-1/2/3), and two G protein-coupled receptor (GPCR) subtypes-endothelin receptor A (ETR) and B (ETR). Since ET-1, the first endothelin, was identified in 1988 as one of the most potent endothelial cell-derived vasoconstrictor peptides with long-lasting actions, the endothelin system has attracted extensive attention due to its critical role in vasoregulation and close relevance in cardiovascular-related diseases. Here we present three cryo-electron microscopy structures of ETR and ETR bound to ET-1 and ETR bound to the selective peptide IRL1620. These structures reveal a highly conserved recognition mode of ET-1 and characterize the ligand selectivity by ETRs. They also present several conformation features of the active ETRs, thus revealing a specific activation mechanism. Together, these findings deepen our understanding of endothelin system regulation and offer an opportunity to design selective drugs targeting specific ETR subtypes.
History
DepositionNov 2, 2022-
Header (metadata) releaseMar 22, 2023-
Map releaseMar 22, 2023-
UpdateOct 4, 2023-
Current statusOct 4, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_34663.png

Downloads & links

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Map

FileDownload / File: emd_34663.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.824 Å
Density
Contour LevelBy AUTHOR: 0.266
Minimum - Maximum-0.051310137 - 1.7767484
Average (Standard dev.)0.002035144 (±0.03167192)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 210.944 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_34663_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_34663_half_map_2.map
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 : ET1-ETAR-Gq-scFv16 complex

EntireName: ET1-ETAR-Gq-scFv16 complex
Components
  • Complex: ET1-ETAR-Gq-scFv16 complex
    • Protein or peptide: Endothelin-1 receptor,Oplophorus-luciferin 2-monooxygenase catalytic subunit chimera
    • Protein or peptide: Endothelin-1Endothelin 1
    • Protein or peptide: Guanine nucleotide-binding protein G(q) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: scFv16
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Supramolecule #1: ET1-ETAR-Gq-scFv16 complex

SupramoleculeName: ET1-ETAR-Gq-scFv16 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #6, #5, #1-#4
Source (natural)Organism: Homo (humans)

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

MacromoleculeName: Guanine nucleotide-binding protein G(q) subunit alpha-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.084832 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA ...String:
MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA RYTTPEDATP EPGEDPRVTR AKYFIRKEFV DISTASGDGR HICYPHFTCA VDTENARRIF NDCKDIILQM NL REYNLV

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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: 41.055867 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI ...String:
MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CRQTFTGHES DI NAICFFP NGNAFATGSD DATCRLFDLR ADQELMTYSH DNIICGITSV SFSKSGRLLL AGYDDFNCNV WDALKADRAG VLA GHDNRV SCLGVTDDGM AVATGSWDSF LKIWNGSSGG GGSGGGGSSG VSGWRLFKKI S

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

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Macromolecule #3: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 30.363043 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFAVQ LVESGGGLVQ PGGSRKLSCS ASGFAFSSFG MHWVRQAPEK GLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA MYYCVRSIYY YGSSPFDFWG QGTTLTVSAG G GGSGGGGS ...String:
MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFAVQ LVESGGGLVQ PGGSRKLSCS ASGFAFSSFG MHWVRQAPEK GLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA MYYCVRSIYY YGSSPFDFWG QGTTLTVSAG G GGSGGGGS GGGGSADIVM TQATSSVPVT PGESVSISCR SSKSLLHSNG NTYLYWFLQR PGQSPQLLIY RMSNLASGVP DR FSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GAGTKLEL

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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: Spodoptera frugiperda (fall armyworm)
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: Endothelin-1

MacromoleculeName: Endothelin-1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.497951 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
CSCSSLMDKE CVYFCHLDII W

UniProtKB: Endothelin-1

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Macromolecule #6: Endothelin-1 receptor,Oplophorus-luciferin 2-monooxygenase cataly...

MacromoleculeName: Endothelin-1 receptor,Oplophorus-luciferin 2-monooxygenase catalytic subunit chimera
type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO / EC number: Oplophorus-luciferin 2-monooxygenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 69.969906 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDSKGSSQKG SRLLLLLVVS NLLLCQGVVS DYKDDDDVDM GQPGNGSAFL LAPNGSHAPD HDVTQQRDEE NLYFQGASDN PERYSTNLS NHVDDFTTFR GTELSFLVTT HQPTNLVLPS NGSMHNYCPQ QTKITSAFKY INTVISCTIF IVGMVGNATL L RIIYQNKC ...String:
MDSKGSSQKG SRLLLLLVVS NLLLCQGVVS DYKDDDDVDM GQPGNGSAFL LAPNGSHAPD HDVTQQRDEE NLYFQGASDN PERYSTNLS NHVDDFTTFR GTELSFLVTT HQPTNLVLPS NGSMHNYCPQ QTKITSAFKY INTVISCTIF IVGMVGNATL L RIIYQNKC MRNGPNALIA SLALGDLIYV VIDLPINVFK LLAGRWPFDH NDFGVFLCKL FPFLQKSSVG ITVLNLCALS VD RYRAVAS WSRVQGIGIP LVTAIEIVSI WILSFILAIP EAIGFVMVPF EYRGEQHKTC MLNATSKFME FYQDVKDWWL FGF YFCMPL VCTAIFYTLM TCEMLNRRNG SLRIALSEHL KQRREVAKTV FCLVVIFALC WFPLHLSRIL KKTVYNEMDK NRCE LLSFL LLMDYIGINL ATMNSCINPI ALYFVSKKFK NCFQSCLCCC CYQSKSLMTS VPMNGTSIQV FTLEDFVGDW EQTAA YNLD QVLEQGGVSS LLQNLAVSVT PIQRIVRSGE NALKIDIHVI IPYEGLSADQ MAQIEEVFKV VYPVDDHHFK VILPYG TLV IDGVTPNMLN YFGRPYEGIA VFDGKKITVT GTLWNGNKII DERLITPDGS MLFRVTINS

UniProtKB: Endothelin-1 receptor, Oplophorus-luciferin 2-monooxygenase catalytic subunit

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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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 510197

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