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- PDB-8xvi: Cryo-EM structure of ETAR bound with Endothelin1 -

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Basic information

Entry
Database: PDB / ID: 8xvi
TitleCryo-EM structure of ETAR bound with Endothelin1
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Endoglucanase H,Endothelin-1 receptor
  • Endothelin-1
  • Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
  • Nanobody 35
KeywordsSIGNALING 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 receptor activity / peptide hormone secretion / endothelin B receptor binding / 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 receptor activity / peptide hormone secretion / endothelin B receptor binding / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / positive regulation of artery morphogenesis / semaphorin-plexin signaling pathway involved in axon guidance / body fluid secretion / neural crest cell fate commitment / atrial cardiac muscle tissue development / vein smooth muscle contraction / glomerular endothelium development / response to prostaglandin F / sympathetic neuron axon guidance / positive regulation of sarcomere organization / vascular associated smooth muscle cell development / noradrenergic neuron differentiation / positive regulation of renal sodium excretion / histamine secretion / leukocyte activation / maternal process involved in parturition / positive regulation of chemokine-mediated signaling pathway / cardiac chamber formation / rough endoplasmic reticulum lumen / heparin metabolic process / developmental pigmentation / pharyngeal arch artery morphogenesis / regulation of D-glucose transmembrane transport / positive regulation of odontogenesis / epithelial fluid transport / 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 / response to leptin / endothelin receptor signaling pathway / response to acetylcholine / sodium ion homeostasis / response to ozone / podocyte differentiation / positive regulation of cell growth involved in cardiac muscle cell development / podocyte apoptotic process / renal sodium ion absorption / embryonic skeletal system development / left ventricular cardiac muscle tissue morphogenesis / artery smooth muscle contraction / mesenchymal cell apoptotic process / glomerular filtration / protein transmembrane transport / enteric nervous system development / axonogenesis involved in innervation / positive regulation of cation channel activity / cellular response to follicle-stimulating hormone stimulus / cranial skeletal system development / cellular response to luteinizing hormone stimulus / : / regulation of pH / positive regulation of prostaglandin secretion / renal albumin absorption / respiratory gaseous exchange by respiratory system / basal part of cell / cellular response to mineralocorticoid stimulus / positive regulation of smooth muscle contraction / 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 / establishment of endothelial barrier / superoxide anion generation / positive regulation of neutrophil chemotaxis / positive regulation of signaling receptor activity / aorta development / cartilage development / middle ear morphogenesis / cellular response to glucocorticoid stimulus / cellulase / negative regulation of protein metabolic process / prostaglandin biosynthetic process / cellular response to fatty acid / neuromuscular process / nitric oxide transport / beta-glucosidase activity / cellulase activity / positive regulation of heart rate / neuron remodeling
Similarity search - Function
Endothelin receptor A / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / : / Endothelin family / Endothelin family signature. / Endothelin / Carbohydrate binding module family 11 ...Endothelin receptor A / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / : / Endothelin family / Endothelin family signature. / Endothelin / 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 / Glycoside hydrolase, family 5 / Cellulase (glycosyl hydrolase family 5) / Galactose-binding-like domain superfamily / G-protein, gamma subunit / G-protein gamma subunit domain profile. / EF-hand calcium-binding domain. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / 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) / Glycoside hydrolase superfamily / 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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Endothelin-1 / Endoglucanase H / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
Acetivibrio thermocellus ATCC 27405 (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.32 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 1.1Oct 30, 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

Downloads & links

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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
R: Endoglucanase H,Endothelin-1 receptor
T: Endothelin-1


Theoretical massNumber of molelcules
Total (without water)173,8066
Polymers173,8066
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)
#5: Protein Endoglucanase H,Endothelin-1 receptor / Cellulase H / Endo-1 / 4-beta-glucanase H / EgH / Endothelin receptor type A / ET-A / ETA-R / hET-AR


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

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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)
#6: 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 ETA 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: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 114666 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048761
ELECTRON MICROSCOPYf_angle_d0.60911854
ELECTRON MICROSCOPYf_dihedral_angle_d4.6531177
ELECTRON MICROSCOPYf_chiral_restr0.0421329
ELECTRON MICROSCOPYf_plane_restr0.0041513

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