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- EMDB-38706: Cryo-EM structure of ETAR bound with Macitentan -

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Basic information

Entry
Database: EMDB / ID: EMD-38706
TitleCryo-EM structure of ETAR bound with Macitentan
Map data
Sample
  • Complex: Complex of Endothelin receptor type A with macitentan
    • Protein or peptide: anti-BRIL Fab Heavy chain
    • Protein or peptide: anti-BRIL Fab Light chain
    • Protein or peptide: Endoglucanase H,Endothelin-1 receptor,Soluble cytochrome b562
    • Protein or peptide: anti-Fab Nanobody
  • Ligand: 6-[2-(5-bromanylpyrimidin-2-yl)oxyethoxy]-5-(4-bromophenyl)-~{N}-(propylsulfamoyl)pyrimidin-4-amine
KeywordsGPCR / COMPLEX / ETA / MACITENTAN / SIGNALING PROTEIN
Function / homology
Function and homology information


regulation of protein localization to cell leading edge / endothelin receptor activity / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / neural crest cell fate commitment / sympathetic neuron axon guidance / atrial cardiac muscle tissue development / glomerular endothelium development / vascular associated smooth muscle cell development / noradrenergic neuron differentiation ...regulation of protein localization to cell leading edge / endothelin receptor activity / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / neural crest cell fate commitment / sympathetic neuron axon guidance / atrial cardiac muscle tissue development / glomerular endothelium development / vascular associated smooth muscle cell development / noradrenergic neuron differentiation / semaphorin-plexin signaling pathway involved in axon guidance / cardiac chamber formation / heparin metabolic process / pharyngeal arch artery morphogenesis / regulation of D-glucose transmembrane transport / endothelin receptor signaling pathway involved in heart process / cardiac neural crest cell migration involved in outflow tract morphogenesis / sodium ion homeostasis / endothelin receptor signaling pathway / response to acetylcholine / developmental pigmentation / podocyte differentiation / podocyte apoptotic process / renal sodium ion absorption / mesenchymal cell apoptotic process / embryonic skeletal system development / left ventricular cardiac muscle tissue morphogenesis / artery smooth muscle contraction / glomerular filtration / protein transmembrane transport / enteric nervous system development / axonogenesis involved in innervation / positive regulation of cation channel activity / cranial skeletal system development / cellular response to follicle-stimulating hormone stimulus / cellular response to luteinizing hormone stimulus / renal albumin absorption / respiratory gaseous exchange by respiratory system / sympathetic nervous system development / phosphatidylinositol phospholipase C activity / norepinephrine metabolic process / vasoconstriction / embryonic heart tube development / axon extension / establishment of endothelial barrier / aorta development / middle ear morphogenesis / cellulase / neuromuscular process / beta-glucosidase activity / cellulase activity / neuron remodeling / activation of adenylate cyclase activity / branching involved in blood vessel morphogenesis / face development / thyroid gland development / smooth muscle contraction / blood vessel remodeling / canonical Wnt signaling pathway / cellulose catabolic process / protein kinase A signaling / response to amphetamine / regulation of heart rate / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / mitochondrion organization / calcium ion transmembrane transport / electron transport chain / regulation of blood pressure / response to wounding / intracellular calcium ion homeostasis / mitotic cell cycle / phospholipase C-activating G protein-coupled receptor signaling pathway / cellular response to oxidative stress / gene expression / positive regulation of cytosolic calcium ion concentration / G alpha (q) signalling events / positive regulation of canonical NF-kappaB signal transduction / in utero embryonic development / cell population proliferation / periplasmic space / electron transfer activity / response to hypoxia / iron ion binding / G protein-coupled receptor signaling pathway / heme binding / cell surface / signal transduction / extracellular region / plasma membrane
Similarity search - Function
Endothelin receptor A / Endothelin receptor family / : / 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. ...Endothelin receptor A / Endothelin receptor family / : / 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) / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Galactose-binding-like domain superfamily / EF-hand calcium-binding domain. / 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
Similarity search - Domain/homology
Soluble cytochrome b562 / Endoglucanase H / Endothelin-1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.26 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-
UpdateAug 28, 2024-
Current statusAug 28, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_38706.png

Downloads & links

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Map

FileDownload / File: emd_38706.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.)
1.2 Å/pix.
x 256 pix.
= 307.2 Å		1.2 Å/pix.
x 256 pix.
= 307.2 Å		1.2 Å/pix.
x 256 pix.
= 307.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.2 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.038
Minimum - Maximum-0.0016570152 - 2.3576744
Average (Standard dev.)0.00060098176 (±0.017390065)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 307.2 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 Endothelin receptor type A with macitentan

EntireName: Complex of Endothelin receptor type A with macitentan
Components
  • Complex: Complex of Endothelin receptor type A with macitentan
    • Protein or peptide: anti-BRIL Fab Heavy chain
    • Protein or peptide: anti-BRIL Fab Light chain
    • Protein or peptide: Endoglucanase H,Endothelin-1 receptor,Soluble cytochrome b562
    • Protein or peptide: anti-Fab Nanobody
  • Ligand: 6-[2-(5-bromanylpyrimidin-2-yl)oxyethoxy]-5-(4-bromophenyl)-~{N}-(propylsulfamoyl)pyrimidin-4-amine

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Supramolecule #1: Complex of Endothelin receptor type A with macitentan

SupramoleculeName: Complex of Endothelin receptor type A with macitentan / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1, #3-#4, #2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: anti-BRIL Fab Heavy chain

MacromoleculeName: anti-BRIL Fab Heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.577918 KDa
Recombinant expressionOrganism: Mammalian expression vector Flag-MCS-pcDNA3.1 (others)
SequenceString: MGWSCIILFL VATATGVHSE ISEVQLVESG GGLVQPGGSL RLSCAASGFN VVDFSLHWVR QAPGKGLEWV AYISSSSGST SYADSVKGR FTISADTSKN TAYLQMNSLR AEDTAVYYCA RWGYWPGEPW WKAFDYWGQG TLVTVSSAST KGPSVFPLAP S SKSTSGGT ...String:
MGWSCIILFL VATATGVHSE ISEVQLVESG GGLVQPGGSL RLSCAASGFN VVDFSLHWVR QAPGKGLEWV AYISSSSGST SYADSVKGR FTISADTSKN TAYLQMNSLR AEDTAVYYCA RWGYWPGEPW WKAFDYWGQG TLVTVSSAST KGPSVFPLAP S SKSTSGGT AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KV DKKVEPK SCDKTHENLY FQGHHHHHH

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Macromolecule #2: anti-Fab Nanobody

MacromoleculeName: anti-Fab Nanobody / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 15.071431 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
HHHHHHGENL YFQGSQVQLQ ESGGGLVQPG GSLRLSCAAS GRTISRYAMS WFRQAPGKER EFVAVARRSG DGAFYADSVQ GRFTVSRDD AKNTVYLQMN SLKPEDTAVY YCAIDSDTFY SGSYDYWGQG TQVTVSS

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Macromolecule #3: anti-BRIL Fab Light chain

MacromoleculeName: anti-BRIL Fab Light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.575604 KDa
Recombinant expressionOrganism: Mammalian expression vector Flag-MCS-pcDNA3.1 (others)
SequenceString: MGWSCIILFL VATATGVHSS DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGT DFTLTISSLQ PEDFATYYCQ QYLYYSLVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN F YPREAKVQ ...String:
MGWSCIILFL VATATGVHSS DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGT DFTLTISSLQ PEDFATYYCQ QYLYYSLVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN F YPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #4: Endoglucanase H,Endothelin-1 receptor,Soluble cytochrome b562

MacromoleculeName: Endoglucanase H,Endothelin-1 receptor,Soluble cytochrome b562
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO / EC number: cellulase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 89.090867 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAHHHHHH HHHHGRAMAS NYNSGLKIGA WVGTQPSESA IKSFQELQGR KLDIVHQFIN WSTDFSWVR PYADAVYNNG SILMITWEPW EYNTVDIKNG KADAYITRMA QDMKAYGKEI WLRPLHAANG DWYPWAIGYS S RVNTNETY ...String:
MKTIIALSYI FCLVFADYKD DDDAHHHHHH HHHHGRAMAS NYNSGLKIGA WVGTQPSESA IKSFQELQGR KLDIVHQFIN WSTDFSWVR PYADAVYNNG SILMITWEPW EYNTVDIKNG KADAYITRMA QDMKAYGKEI WLRPLHAANG DWYPWAIGYS S RVNTNETY IAAFRHIVDI FRANGATNVK WVFNVNCDNV GNGTSYLGHY PGDNYVDYTS IDGYNWGTTQ SWGSQWQSFD QV FSRAYQA LASINKPIII AEFASAEIGG NKARWITEAY NSIRTSYNKV IAAVWFHENK ETDWRINSSP EALAAYREAI GAE NLYFQG TTHQPTNLVL PSNGSMHNYC PQQTKITSAF KYINTVISCT IFIVGMVGNA TLLRIIYQNK CMRNGPNALI ASLA LGDLI YVVIDLPINV FKLLAGRWPF DHNDFGVFLC KLFPFLQKSS VGITVLNLCA LSVDRYRAVA SWSRVQGIGI PLVTA IEIV SIWILSFILA IPEAIGFVMV PFEYRGEQHK TCMLNATSKF MEFYQDVKDW WLFGFYFCMP LVCTAIFYTL MTCEAR RQL ADLEDNWETL NDNLKVIEKA DNAAQVKDAL TKMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALK LA NEGKVKEAQA AAEQLKTTRN AYIQKYLERA RSTLKQRREV AKTVFCLVVI FALCWFPLHL SRILKKTVYN EMDKNRCE L LSFLLLMDYI GINLATMNSC INPIALYFVS KKFKNCFQSC LCCCCYQSKS LMTSVPMNGT SI

UniProtKB: Endoglucanase H, Endothelin-1 receptor, Soluble cytochrome b562, Endothelin-1 receptor

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Macromolecule #5: 6-[2-(5-bromanylpyrimidin-2-yl)oxyethoxy]-5-(4-bromophenyl)-~{N}-...

MacromoleculeName: 6-[2-(5-bromanylpyrimidin-2-yl)oxyethoxy]-5-(4-bromophenyl)-~{N}-(propylsulfamoyl)pyrimidin-4-amine
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1D5I
Molecular weightTheoretical: 588.273 Da

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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: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 568027
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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