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- EMDB-38705: Cryo-EM structure of ETAR bound with Endothelin1 -

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Entry
Database: EMDB / ID: EMD-38705
TitleCryo-EM structure of ETAR bound with Endothelin1
Map data
Sample
  • Complex: Complex of protein Gs/q with ETA and Endothelin-1
    • Protein or peptide: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • 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
    • Protein or peptide: Nanobody 35
    • Protein or peptide: Endoglucanase H,Endothelin-1 receptor
    • Protein or peptide: Endothelin-1
KeywordsGPCR / COMPLEX / ETA / ENDOTHELIN-1 / SIGNALING PROTEIN
Function / homology
Function and homology information


regulation of protein localization to cell leading edge / : / endothelin A receptor binding / phospholipase D-activating G protein-coupled receptor signaling pathway / rhythmic excitation / negative regulation of phospholipase C/protein kinase C signal transduction / endothelin receptor activity / peptide hormone secretion / endothelin B receptor binding / cellular response to human chorionic gonadotropin stimulus ...regulation of protein localization to cell leading edge / : / endothelin A receptor binding / phospholipase D-activating G protein-coupled receptor signaling pathway / rhythmic excitation / negative regulation of phospholipase C/protein kinase C signal transduction / endothelin receptor activity / peptide hormone secretion / endothelin B receptor binding / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / semaphorin-plexin signaling pathway involved in axon guidance / positive regulation of artery morphogenesis / cellular response to mineralocorticoid stimulus / histamine secretion / neural crest cell fate commitment / vein smooth muscle contraction / glomerular endothelium development / response to prostaglandin F / sympathetic neuron axon guidance / positive regulation of sarcomere organization / noradrenergic neuron differentiation / atrial cardiac muscle tissue development / vascular associated smooth muscle cell development / leukocyte activation / body fluid secretion / maternal process involved in parturition / positive regulation of chemokine-mediated signaling pathway / cardiac chamber formation / rough endoplasmic reticulum lumen / heparin proteoglycan metabolic process / positive regulation of renal sodium excretion / : / pharyngeal arch artery morphogenesis / regulation of D-glucose transmembrane transport / positive regulation of odontogenesis / endothelin receptor signaling pathway involved in heart process / epithelial fluid transport / cardiac neural crest cell migration involved in outflow tract morphogenesis / negative regulation of hormone secretion / response to leptin / Weibel-Palade body / endothelin receptor signaling pathway / response to ozone / response to acetylcholine / podocyte differentiation / podocyte apoptotic process / developmental pigmentation / left ventricular cardiac muscle tissue morphogenesis / positive regulation of cell growth involved in cardiac muscle cell development / renal sodium ion absorption / embryonic skeletal system development / sodium ion homeostasis / enteric nervous system development / mesenchymal cell apoptotic process / positive regulation of cation channel activity / axonogenesis involved in innervation / glomerular filtration / protein transmembrane transport / artery smooth muscle contraction / cellular response to follicle-stimulating hormone stimulus / cellular response to luteinizing hormone stimulus / cranial skeletal system development / renal albumin absorption / positive regulation of prostaglandin secretion / respiratory gaseous exchange by respiratory system / regulation of pH / positive regulation of smooth muscle contraction / basal part of cell / sympathetic nervous system development / response to salt / positive regulation of hormone secretion / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / norepinephrine metabolic process / cellular response to toxic substance / positive regulation of urine volume / regulation of systemic arterial blood pressure by endothelin / vasoconstriction / embryonic heart tube development / dorsal/ventral pattern formation / axon extension / establishment of endothelial barrier / cellulase / signal transduction involved in regulation of gene expression / positive regulation of neutrophil chemotaxis / prostaglandin biosynthetic process / superoxide anion generation / cellular response to glucocorticoid stimulus / aorta development / cartilage development / middle ear morphogenesis / negative regulation of protein metabolic process / cellular response to fatty acid / cellulase activity / nitric oxide transport / neuromuscular process / neuron remodeling / beta-glucosidase activity / branching involved in blood vessel morphogenesis / positive regulation of cardiac muscle hypertrophy
Similarity search - Function
Endothelin receptor A / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / : / Endothelin family / Endothelin family signature. / Endothelin / Carbohydrate binding module family 11 ...Endothelin receptor A / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / : / Endothelin family / Endothelin family signature. / Endothelin / Carbohydrate binding module family 11 / Carbohydrate binding domain (family 11) / Glycosyl hydrolase family 26 / Glycosyl hydrolase family 26 domain / Glycosyl hydrolases family 26 (GH26) domain profile. / : / Clostridium cellulosome enzymes repeated domain signature. / Glycoside hydrolase, family 5, conserved site / Glycosyl hydrolases family 5 signature. / Dockerin domain / Dockerin domain profile. / Dockerin type I domain / Dockerin type I repeat / Dockerin domain superfamily / Glycoside hydrolase, family 5 / Cellulase (glycosyl hydrolase family 5) / Galactose-binding-like domain superfamily / EF-hand calcium-binding domain. / 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 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) / Glycoside hydrolase superfamily / 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
Similarity search - Domain/homology
Endothelin-1 / Endoglucanase H / 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
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.32 Å
AuthorsHou JY / Liu SH / Wu LJ / Liu ZJ / Hua T
Funding support China, 1 items
OrganizationGrant numberCountry
Not funded China
CitationJournal: Cell Discov / Year: 2024
Title: Structural basis of antagonist selectivity in endothelin receptors.
Authors: Junyi Hou / Shenhui Liu / Xiaodan Zhang / Guowei Tu / Lijie Wu / Yijie Zhang / Hao Yang / Xiangcheng Li / Junlin Liu / Longquan Jiang / Qiwen Tan / Fang Bai / Zhijie Liu / Changhong Miao / Tian Hua / Zhe Luo /
Abstract: Endothelins and their receptors, ET and ET, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ET antagonists, has shown ...Endothelins and their receptors, ET and ET, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ET antagonists, has shown efficacy in treating pulmonary arterial hypertension (PAH) and other cardiovascular- and renal-related diseases. Here we present cryo-electron microscopy structures of ET in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ET antagonist, respectively. Notably, a specialized anti-ET antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ET and ET, and the agonist BQ3020-bound ET, in complex with G, unveil the molecular basis of agonist/antagonist binding modes in endothelin receptors. Key residues that confer antagonist selectivity to endothelin receptors were identified along with the activation mechanism of ET. Furthermore, our results suggest that ECL2 in ET can serve as an epitope for antibody-mediated receptor antagonism. Collectively, these insights establish a robust theoretical framework for the rational design of small-molecule drugs and antibodies with selective activity against endothelin receptors.
History
DepositionJan 15, 2024-
Header (metadata) releaseAug 28, 2024-
Map releaseAug 28, 2024-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_38705.png

Downloads & links

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Map

FileDownload / File: emd_38705.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.96 Å/pix.
x 256 pix.
= 245.76 Å		0.96 Å/pix.
x 256 pix.
= 245.76 Å		0.96 Å/pix.
x 256 pix.
= 245.76 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.96 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.0017759453 - 2.1667588
Average (Standard dev.)0.0013620155 (±0.028048104)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 245.76 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Complex of protein Gs/q with ETA and Endothelin-1

EntireName: Complex of protein Gs/q with ETA and Endothelin-1
Components
  • Complex: Complex of protein Gs/q with ETA and Endothelin-1
    • Protein or peptide: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • 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
    • Protein or peptide: Nanobody 35
    • Protein or peptide: Endoglucanase H,Endothelin-1 receptor
    • Protein or peptide: Endothelin-1

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Supramolecule #1: Complex of protein Gs/q with ETA and Endothelin-1

SupramoleculeName: Complex of protein Gs/q with ETA and Endothelin-1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit...

MacromoleculeName: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 30.464314 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: HHHHHHENLY FQGNSKTEDQ RNEEKAQREA NKKIEKQLQK DKQVYRATHR LLLLGADNSG KSTIVKQMRI LHGGSGGSGG TSGIFETKF QVDKVNFHMF DVGGQRDERR KWIQCFNDVT AIIFVVDSSD YNRLQEALNL FKSIWNNRWL RTISVILFLN K QDLLAEKV ...String:
HHHHHHENLY FQGNSKTEDQ RNEEKAQREA NKKIEKQLQK DKQVYRATHR LLLLGADNSG KSTIVKQMRI LHGGSGGSGG TSGIFETKF QVDKVNFHMF DVGGQRDERR KWIQCFNDVT AIIFVVDSSD YNRLQEALNL FKSIWNNRWL RTISVILFLN K QDLLAEKV LAGKSKIEDY FPEFARYTTP EDATPEPGED PRVTRAKYFI RDEFLRISTA SGDGRHYCYP HFTCAVDTEN AR RIFNDCK DIILQMNLRE YNLV

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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: 38.045629 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: IGRARGFSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSAS QDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT GYLSCCRFLD D NQIVTSSG ...String:
IGRARGFSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSAS QDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT GYLSCCRFLD D NQIVTSSG DTTCALWDIE TGQQTTTFTG HTGDVMSLSL APDTRLFVSG ACDASAKLWD VREGMCRQTF TGHESDINAI CF FPNGNAF ATGSDDATCR LFDLRADQEL MTYSHDNIIC GITSVSFSKS GRLLLAGYDD FNCNVWDALK ADRAGVLAGH DNR VSCLGV TDDGMAVATG SWDSFLKIWN

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

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Macromolecule #3: 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: 3 / 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 #4: Nanobody 35

MacromoleculeName: Nanobody 35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 17.057271 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MKYLLPTAAA GLLLLAAQPA MAMQVQLQES GGGLVQPGGS LRLSCAASGF TFSNYKMNWV RQAPGKGLEW VSDISQSGAS ISYTGSVKG RFTISRDNAK NTLYLQMNSL KPEDTAVYYC ARCPAPFTRD CFDVTSTTYA YRGQGTQVTV SSHHHHHH

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Macromolecule #5: Endoglucanase H,Endothelin-1 receptor

MacromoleculeName: Endoglucanase H,Endothelin-1 receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO / EC number: cellulase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 77.879422 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAGRAMAS NYNSGLKIGA WVGTQPSESA IKSFQELQGR KLDIVHQFIN WSTDFSWVRP YADAVYNNG SILMITWEPW EYNTVDIKNG KADAYITRMA QDMKAYGKEI WLRPLHAANG DWYPWAIGYS SRVNTNETYI A AFRHIVDI ...String:
MKTIIALSYI FCLVFADYKD DDDAGRAMAS NYNSGLKIGA WVGTQPSESA IKSFQELQGR KLDIVHQFIN WSTDFSWVRP YADAVYNNG SILMITWEPW EYNTVDIKNG KADAYITRMA QDMKAYGKEI WLRPLHAANG DWYPWAIGYS SRVNTNETYI A AFRHIVDI FRANGATNVK WVFNVNCDNV GNGTSYLGHY PGDNYVDYTS IDGYNWGTTQ SWGSQWQSFD QVFSRAYQAL AS INKPIII AEFASAEIGG NKARWITEAY NSIRTSYNKV IAAVWFHENK ETDWRINSSP EALAAYREAI GATTHQPTNL VLP SNGSMH NYCPQQTKIT SAFKYINTVI SCTIFIVGMV GNATLLRIIY QNKCMRNGPN ALIASLALGD LIYVVIDLPI NVFK LLAGR WPFDHNDFGV FLCKLFPFLQ KSSVGITVLN LCALSVDRYR AVASWSRVQG IGIPLVTAIE IVSIWILSFI LAIPE AIGF VMVPFEYRGE QHKTCMLNAT SKFMEFYQDV KDWWLFGFYF CMPLVCTAIF YTLMTCEMLN RRNGSLRIAL SEHLKQ RRE VAKTVFCLVV IFALCWFPLH LSRILKKTVY NEMDKNRCEL LSFLLLMDYI GINLATMNSC INPIALYFVS KKFKNCF QS CLCCCCYQSK SLMTSVPMNG TSILEVLFQG PHHHHHHHHH H

UniProtKB: Endoglucanase H, Endothelin-1 receptor

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Macromolecule #6: Endothelin-1

MacromoleculeName: Endothelin-1 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.497951 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
CSCSSLMDKE CVYFCHLDII W

UniProtKB: Endothelin-1

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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: FEI FALCON IV (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 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: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 114666
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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