+Open data
-Basic information
Entry | Database: PDB / ID: 8xvi | ||||||
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Title | Cryo-EM structure of ETAR bound with Endothelin1 | ||||||
Components |
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Keywords | SIGNALING PROTEIN / GPCR / COMPLEX / ETA / ENDOTHELIN-1 | ||||||
Function / homology | Function and homology information regulation of protein localization to cell leading edge / positive regulation of prostaglandin-endoperoxide synthase activity / endothelin A receptor binding / protein kinase C deactivation / phospholipase D-activating G protein-coupled receptor signaling pathway / rhythmic excitation / endothelin B receptor binding / endothelin receptor activity / peptide hormone secretion / cellular response to human chorionic gonadotropin stimulus ...regulation of protein localization to cell leading edge / positive regulation of prostaglandin-endoperoxide synthase activity / endothelin A receptor binding / protein kinase C deactivation / phospholipase D-activating G protein-coupled receptor signaling pathway / rhythmic excitation / endothelin B receptor binding / endothelin receptor activity / peptide hormone secretion / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / positive regulation of artery morphogenesis / body fluid secretion / neural crest cell fate commitment / vein smooth muscle contraction / sympathetic neuron axon guidance / atrial cardiac muscle tissue development / response to prostaglandin F / glomerular endothelium development / positive regulation of sarcomere organization / vascular associated smooth muscle cell development / noradrenergic neuron differentiation / semaphorin-plexin signaling pathway involved in axon guidance / histamine secretion / positive regulation of renal sodium excretion / leukocyte activation / positive regulation of chemokine-mediated signaling pathway / cardiac chamber formation / maternal process involved in parturition / heparin metabolic process / rough endoplasmic reticulum lumen / pharyngeal arch artery morphogenesis / regulation of D-glucose transmembrane transport / positive regulation of odontogenesis / epithelial fluid transport / response to leptin / endothelin receptor signaling pathway involved in heart process / negative regulation of hormone secretion / cardiac neural crest cell migration involved in outflow tract morphogenesis / Weibel-Palade body / sodium ion homeostasis / endothelin receptor signaling pathway / response to acetylcholine / response to ozone / developmental pigmentation / podocyte differentiation / positive regulation of cell growth involved in cardiac muscle cell development / 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 / positive regulation of prostaglandin secretion / cellular response to luteinizing hormone stimulus / negative regulation of nitric-oxide synthase biosynthetic process / cellular response to mineralocorticoid stimulus / renal albumin absorption / basal part of cell / positive regulation of smooth muscle contraction / respiratory gaseous exchange by respiratory system / regulation of pH / sympathetic nervous system development / response to salt / positive regulation of urine volume / phosphatidylinositol phospholipase C activity / positive regulation of hormone secretion / norepinephrine metabolic process / regulation of systemic arterial blood pressure by endothelin / vasoconstriction / : / negative regulation of blood coagulation / embryonic heart tube development / dorsal/ventral pattern formation / axon extension / superoxide anion generation / establishment of endothelial barrier / positive regulation of neutrophil chemotaxis / aorta development / positive regulation of signaling receptor activity / cartilage development / middle ear morphogenesis / : / cellular response to glucocorticoid stimulus / negative regulation of protein metabolic process / cellulase / prostaglandin biosynthetic process / cellular response to fatty acid / neuromuscular process / nitric oxide transport / beta-glucosidase activity / positive regulation of heart rate / cellulase activity Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Lama glama (llama) Acetivibrio thermocellus ATCC 27405 (bacteria) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.32 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 | 8xvi.cif.gz | 235.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8xvi.ent.gz | 179 KB | Display | PDB format |
PDBx/mmJSON format | 8xvi.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8xvi_validation.pdf.gz | 1.4 MB | Display | wwPDB validaton report |
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Full document | 8xvi_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 8xvi_validation.xml.gz | 44.4 KB | Display | |
Data in CIF | 8xvi_validation.cif.gz | 66 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/xv/8xvi ftp://data.pdbj.org/pub/pdb/validation_reports/xv/8xvi | HTTPS FTP |
-Related structure data
Related structure data | 38705MC 8xveC 8xvhC 8xvjC 8xvkC 8xvlC 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
-Protein , 2 types, 2 molecules AR
#1: Protein | 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) |
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#5: Protein | 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 |
-Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG
#2: Protein | 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 |
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#3: Protein | 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 |
-Antibody / Protein/peptide , 2 types, 2 molecules NT
#4: Antibody | 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) |
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#6: Protein/peptide | 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 |
-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 protein Gs/q with ETA and Endothelin-1 / Type: COMPLEX / Entity ID: all / 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
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
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: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 114666 / Symmetry type: POINT | ||||||||||||||||||||||||
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