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- PDB-8xvl: Cryo-EM structure of ETAR bound with Zibotentan -

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Basic information

Entry
Database: PDB / ID: 8xvl
TitleCryo-EM structure of ETAR bound with Zibotentan
Components
  • Endoglucanase H,Endothelin-1 receptor,Soluble cytochrome b562
  • anti-BRIL Fab Heavy chain
  • anti-BRIL Fab Light chain
  • anti-Fab Nanobody
KeywordsSIGNALING PROTEIN / GPCR / COMPLEX / ETA / ZIBOTENTAN
Function / homology
Function and homology information


regulation of protein localization to cell leading edge / mesenchymal cell apoptotic process / endothelin receptor activity / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / glomerular endothelium development / neural crest cell fate commitment / sympathetic neuron axon guidance / noradrenergic neuron differentiation / vascular associated smooth muscle cell development ...regulation of protein localization to cell leading edge / mesenchymal cell apoptotic process / endothelin receptor activity / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / glomerular endothelium development / neural crest cell fate commitment / sympathetic neuron axon guidance / noradrenergic neuron differentiation / vascular associated smooth muscle cell development / cardiac chamber formation / atrial cardiac muscle tissue development / middle ear morphogenesis / developmental pigmentation / pharyngeal arch artery morphogenesis / podocyte differentiation / heparin proteoglycan metabolic process / embryonic skeletal system development / cardiac neural crest cell migration involved in outflow tract morphogenesis / glomerular filtration / podocyte apoptotic process / left ventricular cardiac muscle tissue morphogenesis / sodium ion homeostasis / respiratory gaseous exchange by respiratory system / renal albumin absorption / cranial skeletal system development / response to acetylcholine / protein transmembrane transport / renal sodium ion absorption / axonogenesis involved in innervation / norepinephrine metabolic process / embryonic heart tube development / artery smooth muscle contraction / cellular response to follicle-stimulating hormone stimulus / endothelin receptor signaling pathway / sympathetic nervous system development / smooth muscle contraction / enteric nervous system development / cellular response to luteinizing hormone stimulus / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / axon extension / positive regulation of cation channel activity / vasoconstriction / heart process / aorta development / branching involved in blood vessel morphogenesis / cellulase / cellular response to toxic substance / establishment of endothelial barrier / neuromuscular process / cellulase activity / face development / thyroid gland development / beta-glucosidase activity / neuron remodeling / canonical Wnt signaling pathway / blood vessel remodeling / semaphorin-plexin signaling pathway / cellulose catabolic process / cAMP/PKA signal transduction / activation of adenylate cyclase activity / regulation of heart rate / response to amphetamine / Peptide ligand-binding receptors / mitochondrion organization / electron transport chain / response to wounding / cell population proliferation / intracellular calcium ion homeostasis / regulation of blood pressure / gene expression / calcium ion transmembrane transport / phospholipase C-activating G protein-coupled receptor signaling pathway / mitotic cell cycle / positive regulation of cytosolic calcium ion concentration / cellular response to oxidative stress / G alpha (q) signalling events / electron transfer activity / periplasmic space / 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 / Cellulase (glycosyl hydrolase family 5) / Glycoside 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. / 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
Similarity search - Domain/homology
: / Soluble cytochrome b562 / Endoglucanase H / Endothelin-1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
Acetivibrio thermocellus (bacteria)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.22 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
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 20, 2024Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / em_admin ...chem_comp / em_admin / entity / pdbx_entity_nonpoly
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _em_admin.last_update / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
H: anti-BRIL Fab Heavy chain
K: anti-Fab Nanobody
L: anti-BRIL Fab Light chain
R: Endoglucanase H,Endothelin-1 receptor,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)158,7405
Polymers158,3164
Non-polymers4241
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Antibody anti-BRIL Fab Heavy chain


Mass: 28577.918 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Production host: Mammalian expression vector Flag-MCS-pcDNA3.1 (others)
#2: Antibody anti-Fab Nanobody


Mass: 15071.431 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#3: Antibody anti-BRIL Fab Light chain


Mass: 25575.604 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Production host: Mammalian expression vector Flag-MCS-pcDNA3.1 (others)
#4: Protein Endoglucanase H,Endothelin-1 receptor,Soluble cytochrome b562 / Cellulase H / Endo-1 / 4-beta-glucanase H / EgH / Endothelin receptor type A / ET-A / ETA-R / hET- ...Cellulase H / Endo-1 / 4-beta-glucanase H / EgH / Endothelin receptor type A / ET-A / ETA-R / hET-AR / Cytochrome b-562


Mass: 89090.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) (bacteria), (gene. exp.) Homo sapiens (human), (gene. exp.) ...Source: (gene. exp.) Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) (bacteria), (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: celH, Cthe_1472, EDNRA, ETA, ETRA, cybC / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P16218, UniProt: P25101, UniProt: P0ABE7, cellulase
#5: Chemical ChemComp-A1D5L / Zibotentan


Mass: 424.433 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16N6O4S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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 Endothelin receptor type A with Zibotentan / Type: COMPLEX / Entity ID: #1-#4 / 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

MicroscopyModel: FEI TITAN
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

CTF correctionType: NONE
3D reconstructionResolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 644807 / Symmetry type: POINT

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