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- PDB-8hcq: Cryo-EM structure of endothelin1-bound ETAR-Gq complex -

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Basic information

Entry
Database: PDB / ID: 8hcq
TitleCryo-EM structure of endothelin1-bound ETAR-Gq complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Endothelin-1 receptor,Oplophorus-luciferin 2-monooxygenase catalytic subunit chimera
  • Endothelin-1Endothelin 1
  • scFv16
KeywordsMEMBRANE PROTEIN / ET1 / ETAR / Gq / scFv16
Function / homology
Function and homology information


regulation of protein localization to cell leading edge / : / endothelin receptor activity / positive regulation of prostaglandin-endoperoxide synthase activity / endothelin A receptor binding / protein kinase C deactivation / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / phospholipase D-activating G protein-coupled receptor signaling pathway / endothelin B receptor binding ...regulation of protein localization to cell leading edge / : / endothelin receptor activity / positive regulation of prostaglandin-endoperoxide synthase activity / endothelin A receptor binding / protein kinase C deactivation / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / phospholipase D-activating G protein-coupled receptor signaling pathway / endothelin B receptor binding / rhythmic excitation / peptide hormone secretion / neural crest cell fate commitment / sympathetic neuron axon guidance / Oplophorus-luciferin 2-monooxygenase / body fluid secretion / Oplophorus-luciferin 2-monooxygenase activity / glomerular endothelium development / vein smooth muscle contraction / noradrenergic neuron differentiation / response to prostaglandin F / positive regulation of renal sodium excretion / leukocyte activation / positive regulation of sarcomere organization / vascular associated smooth muscle cell development / atrial cardiac muscle tissue development / histamine secretion / heparin metabolic process / rough endoplasmic reticulum lumen / positive regulation of chemokine-mediated signaling pathway / positive regulation of odontogenesis / maternal process involved in parturition / cardiac chamber formation / pharyngeal arch artery morphogenesis / regulation of glucose transmembrane transport / endothelin receptor signaling pathway involved in heart process / semaphorin-plexin signaling pathway involved in axon guidance / epithelial fluid transport / podocyte differentiation / cardiac neural crest cell migration involved in outflow tract morphogenesis / negative regulation of hormone secretion / protein transmembrane transport / response to leptin / endothelin receptor signaling pathway / response to ozone / sodium ion homeostasis / Weibel-Palade body / developmental pigmentation / response to acetylcholine / renal sodium ion absorption / positive regulation of cell growth involved in cardiac muscle cell development / mesenchymal cell apoptotic process / glomerular filtration / artery smooth muscle contraction / podocyte apoptotic process / left ventricular cardiac muscle tissue morphogenesis / embryonic skeletal system development / axonogenesis involved in innervation / enteric nervous system development / positive regulation of cation channel activity / positive regulation of prostaglandin secretion / renal albumin absorption / cellular response to follicle-stimulating hormone stimulus / cellular response to luteinizing hormone stimulus / cranial skeletal system development / regulation of pH / negative regulation of nitric-oxide synthase biosynthetic process / cellular response to mineralocorticoid stimulus / positive regulation of urine volume / respiratory gaseous exchange by respiratory system / basal part of cell / positive regulation of smooth muscle contraction / sympathetic nervous system development / phosphatidylinositol phospholipase C activity / norepinephrine metabolic process / positive regulation of hormone secretion / regulation of systemic arterial blood pressure by endothelin / vasoconstriction / protein kinase C-activating G protein-coupled receptor signaling pathway / embryonic heart tube development / negative regulation of blood coagulation / axon extension / superoxide anion generation / dorsal/ventral pattern formation / establishment of endothelial barrier / positive regulation of neutrophil chemotaxis / middle ear morphogenesis / positive regulation of signaling receptor activity / cellular response to glucocorticoid stimulus / cartilage development / aorta development / prostaglandin biosynthetic process / neuromuscular process / negative regulation of protein metabolic process / nitric oxide transport / cellular response to fatty acid / neuron remodeling / cellular response to organic substance / branching involved in blood vessel morphogenesis / positive regulation of heart rate
Similarity search - Function
Endothelin receptor A / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / Endothelin family / Endothelin family signature. / Endothelin / Calycin / G-protein, gamma subunit ...Endothelin receptor A / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / Endothelin family / Endothelin family signature. / Endothelin / Calycin / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Endothelin-1 / 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 / Oplophorus-luciferin 2-monooxygenase catalytic subunit
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsYuan, Q. / Jiang, Y. / Xu, H.E. / Ji, Y. / Duan, J.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis of peptide recognition and activation of endothelin receptors.
Authors: Yujie Ji / Jia Duan / Qingning Yuan / Xinheng He / Gong Yang / Shengnan Zhu / Kai Wu / Wen Hu / Tianyu Gao / Xi Cheng / Hualiang Jiang / H Eric Xu / Yi Jiang /
Abstract: Endothelin system comprises three endogenous 21-amino-acid peptide ligands endothelin-1, -2, and -3 (ET-1/2/3), and two G protein-coupled receptor (GPCR) subtypes-endothelin receptor A (ETR) and B ...Endothelin system comprises three endogenous 21-amino-acid peptide ligands endothelin-1, -2, and -3 (ET-1/2/3), and two G protein-coupled receptor (GPCR) subtypes-endothelin receptor A (ETR) and B (ETR). Since ET-1, the first endothelin, was identified in 1988 as one of the most potent endothelial cell-derived vasoconstrictor peptides with long-lasting actions, the endothelin system has attracted extensive attention due to its critical role in vasoregulation and close relevance in cardiovascular-related diseases. Here we present three cryo-electron microscopy structures of ETR and ETR bound to ET-1 and ETR bound to the selective peptide IRL1620. These structures reveal a highly conserved recognition mode of ET-1 and characterize the ligand selectivity by ETRs. They also present several conformation features of the active ETRs, thus revealing a specific activation mechanism. Together, these findings deepen our understanding of endothelin system regulation and offer an opportunity to design selective drugs targeting specific ETR subtypes.
History
DepositionNov 2, 2022Deposition site: PDBJ / Processing site: RCSB
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(q) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
E: scFv16
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
L: Endothelin-1
R: Endothelin-1 receptor,Oplophorus-luciferin 2-monooxygenase catalytic subunit chimera


Theoretical massNumber of molelcules
Total (without water)179,8336
Polymers179,8336
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(q) subunit alpha-1


Mass: 28084.832 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 41055.867 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
#4: 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 / Protein , 3 types, 3 molecules ELR

#3: Antibody scFv16


Mass: 30363.043 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein/peptide Endothelin-1 / Endothelin 1 / Preproendothelin-1 / PPET1


Mass: 2497.951 Da / Num. of mol.: 1 / Fragment: UNP residues 53-73
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EDN1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P05305
#6: Protein Endothelin-1 receptor,Oplophorus-luciferin 2-monooxygenase catalytic subunit chimera / Endothelin receptor type A / ET-A / ETA-R / hET-AR / 19kOLase


Mass: 69969.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EDNRA, ETA, ETRA / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P25101, UniProt: Q9GV45, Oplophorus-luciferin 2-monooxygenase

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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: ET1-ETAR-Gq-scFv16 complex / Type: COMPLEX / Entity ID: #6, #5, #1-#4 / Source: MULTIPLE SOURCES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo (humans)9605
31Mus musculus (house mouse)10090
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 FIELDBright-field microscopy / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 510197 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039308
ELECTRON MICROSCOPYf_angle_d0.58112596
ELECTRON MICROSCOPYf_dihedral_angle_d3.7991250
ELECTRON MICROSCOPYf_chiral_restr0.0391416
ELECTRON MICROSCOPYf_plane_restr0.0051598

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