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- PDB-8xvh: Cryo-EM structure of ETBR bound with Endothelin1 -

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Basic information

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


enteric smooth muscle cell differentiation / chordate pharynx development / response to endothelin / aldosterone metabolic process / negative regulation of neuron maturation / endothelin A receptor binding / negative regulation of phospholipase C/protein kinase C signal transduction / endothelin receptor activity / peptide hormone secretion / endothelin B receptor binding ...enteric smooth muscle cell differentiation / chordate pharynx development / response to endothelin / aldosterone metabolic process / negative regulation of neuron maturation / endothelin A receptor binding / 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 / glomerular endothelium development / positive regulation of artery morphogenesis / neural crest cell fate commitment / regulation of fever generation / vein smooth muscle contraction / response to prostaglandin F / sympathetic neuron axon guidance / noradrenergic neuron differentiation / positive regulation of odontogenesis / histamine secretion / positive regulation of penile erection / positive regulation of chemokine-mediated signaling pathway / maternal process involved in parturition / leukocyte activation / rough endoplasmic reticulum lumen / developmental pigmentation / positive regulation of sarcomere organization / pharyngeal arch artery morphogenesis / podocyte differentiation / epithelial fluid transport / heparin proteoglycan metabolic process / negative regulation of hormone secretion / cardiac neural crest cell migration involved in outflow tract morphogenesis / positive regulation of cell growth involved in cardiac muscle cell development / Weibel-Palade body / glomerular filtration / cGMP biosynthetic process / response to ozone / renal sodium excretion / renin secretion into blood stream / renal albumin absorption / response to leptin / regulation of systemic arterial blood pressure by endothelin / response to sodium phosphate / positive regulation of prostaglandin secretion / protein transmembrane transport / renal sodium ion absorption / axonogenesis involved in innervation / melanocyte differentiation / embryonic heart tube development / positive regulation of hormone secretion / artery smooth muscle contraction / cellular response to follicle-stimulating hormone stimulus / endothelin receptor signaling pathway / enteric nervous system development / cellular response to luteinizing hormone stimulus / positive regulation of prostaglandin biosynthetic process / cellular response to mineralocorticoid stimulus / axon extension / positive regulation of smooth muscle contraction / positive regulation of cation channel activity / vasoconstriction / regulation of epithelial cell proliferation / response to salt / basal part of cell / signal transduction involved in regulation of gene expression / type 1 angiotensin receptor binding / negative regulation of adenylate cyclase activity / ganglioside catabolic process / heart process / cellular response to toxic substance / negative regulation of protein metabolic process / cellular response to fatty acid / macrophage chemotaxis / oligosaccharide catabolic process / establishment of endothelial barrier / superoxide anion generation / response to pain / positive regulation of neutrophil chemotaxis / positive regulation of urine volume / cellular response to glucocorticoid stimulus / nitric oxide transport / thyroid gland development / response to dexamethasone / response to testosterone / positive regulation of cardiac muscle hypertrophy / exo-alpha-sialidase / canonical Wnt signaling pathway / exo-alpha-sialidase activity / negative regulation of smooth muscle cell apoptotic process / peptide hormone binding / positive regulation of cell size / response to amino acid / semaphorin-plexin signaling pathway / negative regulation of blood coagulation / cellular response to interleukin-1 / cellular response to transforming growth factor beta stimulus / membrane depolarization
Similarity search - Function
Endothelin receptor B / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / : / Endothelin family / Endothelin family signature. / Endothelin / BNR repeat-like domain ...Endothelin receptor B / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / : / Endothelin family / Endothelin family signature. / Endothelin / BNR repeat-like domain / Glycoside hydrolase, family 33, N-terminal / Trans-sialidase, domain 3 / Sialidase, N-terminal domain / Sialidase family / Sialidase / Sialidase superfamily / Serpentine type 7TM GPCR chemoreceptor Srsx / 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. / Concanavalin A-like lectin/glucanase domain superfamily / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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 / Endothelin receptor type B / 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 / exo-alpha-sialidase
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
Clostridium perfringens (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.26 Å
AuthorsHou, J.Y. / Liu, S.H. / Wu, L.J. / Liu, Z.J. / Hua, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
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 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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
T: Endothelin-1
R: Exo-alpha-sialidase,Endothelin receptor type B


Theoretical massNumber of molelcules
Total (without water)190,0506
Polymers190,0506
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)
#6: Protein Exo-alpha-sialidase,Endothelin receptor type B / ET-B / ET-BR / Endothelin receptor non-selective type


Mass: 94123.805 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Clostridium perfringens (bacteria), (gene. exp.) Homo sapiens (human)
Gene: nanH, EDNRB, ETRB / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q59310, UniProt: P24530, exo-alpha-sialidase

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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)
#5: 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 ETB 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

CTF correctionType: NONE
3D reconstructionResolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 209838 / Symmetry type: POINT

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