+Open data
-Basic information
Entry | Database: PDB / ID: 8xvl | ||||||
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Title | Cryo-EM structure of ETAR bound with Zibotentan | ||||||
Components |
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Keywords | SIGNALING PROTEIN / GPCR / COMPLEX / ETA / ZIBOTENTAN | ||||||
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 | ||||||
Biological species | Homo sapiens (human) synthetic construct (others) Acetivibrio thermocellus (bacteria) Escherichia coli (E. coli) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.22 Å | ||||||
Authors | Hou, J.Y. / Liu, S.H. / Wu, L.J. / Liu, Z.J. / Hua, T. | ||||||
Funding support | China, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8xvl.cif.gz | 208.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8xvl.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 8xvl.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8xvl_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 8xvl_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 8xvl_validation.xml.gz | 45.2 KB | Display | |
Data in CIF | 8xvl_validation.cif.gz | 66.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/xv/8xvl ftp://data.pdbj.org/pub/pdb/validation_reports/xv/8xvl | HTTPS FTP |
-Related structure data
Related structure data | 38708MC 8xveC 8xvhC 8xviC 8xvjC 8xvkC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Antibody | 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) |
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#2: Antibody | 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 | 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 | 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 / ~{ Mass: 424.433 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16N6O4S / Feature type: SUBJECT OF INVESTIGATION |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Complex of Endothelin receptor type A with Zibotentan / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Microscopy | Model: FEI TITAN |
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Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
-Processing
CTF correction | Type: NONE |
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3D reconstruction | Resolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 644807 / Symmetry type: POINT |