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- PDB-8xvi: Cryo-EM structure of ETAR bound with Endothelin1 -

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Entry
Database: PDB / ID: 8xvi
TitleCryo-EM structure of ETAR bound with Endothelin1
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Endoglucanase H,Endothelin-1 receptor
  • Endothelin-1
  • Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
  • Nanobody 35
KeywordsSIGNALING PROTEIN / GPCR / COMPLEX / ETA / ENDOTHELIN-1
Function / homology
Function and homology information


regulation of protein localization to cell leading edge / : / endothelin A receptor binding / 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 ...regulation of protein localization to cell leading edge / : / endothelin A receptor binding / 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 / 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 / vascular associated smooth muscle cell development / positive regulation of chemokine-mediated signaling pathway / cardiac chamber formation / leukocyte activation / maternal process involved in parturition / phospholipase D-activating G protein-coupled receptor signaling pathway / rough endoplasmic reticulum lumen / atrial cardiac muscle tissue development / body fluid secretion / pharyngeal arch artery morphogenesis / regulation of D-glucose transmembrane transport / endothelin receptor signaling pathway involved in heart process / positive regulation of odontogenesis / epithelial fluid transport / cardiac neural crest cell migration involved in outflow tract morphogenesis / heparin proteoglycan metabolic process / negative regulation of hormone secretion / response to ozone / Weibel-Palade body / podocyte differentiation / endothelin receptor signaling pathway / podocyte apoptotic process / positive regulation of cation channel activity / left ventricular cardiac muscle tissue morphogenesis / developmental pigmentation / embryonic skeletal system development / positive regulation of cell growth involved in cardiac muscle cell development / sodium ion homeostasis / response to leptin / mesenchymal cell apoptotic process / response to acetylcholine / axonogenesis involved in innervation / glomerular filtration / enteric nervous system development / positive regulation of smooth muscle contraction / renal sodium ion absorption / renal albumin absorption / cellular response to follicle-stimulating hormone stimulus / artery smooth muscle contraction / positive regulation of prostaglandin secretion / protein transmembrane transport / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / cellular response to luteinizing hormone stimulus / regulation of pH / cellular response to mineralocorticoid stimulus / respiratory gaseous exchange by respiratory system / sympathetic nervous system development / vasoconstriction / basal part of cell / positive regulation of renal sodium excretion / cranial skeletal system development / response to salt / norepinephrine metabolic process / positive regulation of hormone secretion / regulation of systemic arterial blood pressure by endothelin / cellular response to toxic substance / dorsal/ventral pattern formation / embryonic heart tube development / axon extension / cellular response to fatty acid / cellulase / cartilage development / establishment of endothelial barrier / prostaglandin biosynthetic process / positive regulation of neutrophil chemotaxis / positive regulation of urine volume / signal transduction involved in regulation of gene expression / superoxide anion generation / negative regulation of protein metabolic process / cellulase activity / cellular response to glucocorticoid stimulus / nitric oxide transport / aorta development / beta-glucosidase activity / middle ear morphogenesis / branching involved in blood vessel morphogenesis / response to dexamethasone / neuron remodeling / neuromuscular process / 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 / Cellulase (glycosyl hydrolase family 5) / Glycoside 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / Glycoside hydrolase superfamily / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / 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)
Acetivibrio thermocellus ATCC 27405 (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.32 Å
AuthorsHou, J.Y. / Liu, S.H. / Wu, L.J. / Liu, Z.J. / Hua, T.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 28, 2024Provider: repository / Type: Initial release
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Revision 1.1Oct 30, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update
Revision 1.2Jul 23, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nanobody 35
R: Endoglucanase H,Endothelin-1 receptor
T: Endothelin-1


Theoretical massNumber of molelcules
Total (without water)173,8066
Polymers173,8066
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AR

#1: Protein Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short


Mass: 30464.314 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#5: Protein Endoglucanase H,Endothelin-1 receptor / Cellulase H / Endo-1 / 4-beta-glucanase H / EgH / Endothelin receptor type A / ET-A / ETA-R / hET-AR


Mass: 77879.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Acetivibrio thermocellus ATCC 27405 (bacteria), (gene. exp.) Homo sapiens (human)
Gene: celH, Cthe_1472, EDNRA, ETA, ETRA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P16218, UniProt: P25101, cellulase

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38045.629 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody / Protein/peptide , 2 types, 2 molecules NT

#4: Antibody Nanobody 35


Mass: 17057.271 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#6: Protein/peptide Endothelin-1 / ET-1


Mass: 2497.951 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EDN1 / Production host: Homo sapiens (human) / References: UniProt: P05305

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Details

Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Complex of protein Gs/q with ETA and Endothelin-1 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 114666 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048761
ELECTRON MICROSCOPYf_angle_d0.60911854
ELECTRON MICROSCOPYf_dihedral_angle_d4.6531177
ELECTRON MICROSCOPYf_chiral_restr0.0421329
ELECTRON MICROSCOPYf_plane_restr0.0041513

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