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- PDB-8xwp: Cryo-EM structure of ET-1 bound ETBR-DNGI complex -

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Basic information

Entry
Database: PDB / ID: 8xwp
TitleCryo-EM structure of ET-1 bound ETBR-DNGI complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Endothelin receptor type B
  • Endothelin-1
  • SCFV16
KeywordsMEMBRANE PROTEIN / ENDOTHELIN / RECEPTOR / Gi / COMPLEX
Function / homology
Function and homology information


enteric smooth muscle cell differentiation / response to endothelin / negative regulation of neuron maturation / endothelin A receptor binding / chordate pharynx development / negative regulation of phospholipase C/protein kinase C signal transduction / endothelin receptor activity / peptide hormone secretion / endothelin B receptor binding / aldosterone metabolic process ...enteric smooth muscle cell differentiation / response to endothelin / negative regulation of neuron maturation / endothelin A receptor binding / chordate pharynx development / negative regulation of phospholipase C/protein kinase C signal transduction / endothelin receptor activity / peptide hormone secretion / endothelin B receptor binding / aldosterone metabolic process / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / 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 / glomerular endothelium development / 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 / heparin proteoglycan metabolic process / podocyte differentiation / negative regulation of hormone secretion / cardiac neural crest cell migration involved in outflow tract morphogenesis / epithelial fluid transport / positive regulation of cell growth involved in cardiac muscle cell development / Weibel-Palade body / cGMP biosynthetic process / response to ozone / renal sodium excretion / glomerular filtration / renal albumin absorption / renin secretion into blood stream / response to leptin / regulation of systemic arterial blood pressure by endothelin / response to sodium phosphate / axonogenesis involved in innervation / melanocyte differentiation / renal sodium ion absorption / positive regulation of prostaglandin secretion / positive regulation of hormone secretion / cellular response to follicle-stimulating hormone stimulus / endothelin receptor signaling pathway / artery smooth muscle contraction / embryonic heart tube development / protein transmembrane transport / cellular response to luteinizing hormone stimulus / positive regulation of prostaglandin biosynthetic process / cellular response to mineralocorticoid stimulus / positive regulation of cation channel activity / vasoconstriction / positive regulation of smooth muscle contraction / enteric nervous system development / axon extension / response to salt / type 1 angiotensin receptor binding / basal part of cell / regulation of epithelial cell proliferation / negative regulation of adenylate cyclase activity / signal transduction involved in regulation of gene expression / heart process / cellular response to toxic substance / negative regulation of protein metabolic process / cellular response to fatty acid / 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 / positive regulation of cardiac muscle hypertrophy / response to testosterone / canonical Wnt signaling pathway / negative regulation of smooth muscle cell apoptotic process / macrophage chemotaxis / peptide hormone binding / semaphorin-plexin signaling pathway / response to amino acid / negative regulation of blood coagulation / positive regulation of cell size / membrane depolarization / cellular response to transforming growth factor beta stimulus / cellular response to interleukin-1 / cAMP/PKA signal transduction / ERK1 and ERK2 cascade / regulation of vasoconstriction / response to muscle stretch
Similarity search - Function
Endothelin receptor B / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / : / Endothelin family / Endothelin family signature. / Endothelin / G-protein alpha subunit, group I ...Endothelin receptor B / Endothelin receptor family / Endothelin-like toxin / Endothelin-like toxin, conserved site / Endothelin / : / Endothelin family / Endothelin family signature. / Endothelin / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / 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. / 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 / P-loop containing nucleoside triphosphate hydrolase
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 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.21 Å
AuthorsTani, K. / Maki-Yonekura, S. / Kanno, R. / Negami, T. / Hamaguchi, T. / Hall, M. / Mizoguchi, A. / Humbel, B.M. / Terada, T. / Yonekura, K. / Doi, T.
Funding support Japan, 3items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED)JP21am0101118 Japan
Japan Agency for Medical Research and Development (AMED)JP23ama121004 Japan
Japan Society for the Promotion of Science (JSPS)20H03210 Japan
CitationJournal: Commun Biol / Year: 2024
Title: Structure of endothelin ET receptor-G complex in a conformation stabilized by unique NPxxL motif.
Authors: Kazutoshi Tani / Saori Maki-Yonekura / Ryo Kanno / Tatsuki Negami / Tasuku Hamaguchi / Malgorzata Hall / Akira Mizoguchi / Bruno M Humbel / Tohru Terada / Koji Yonekura / Tomoko Doi /
Abstract: Endothelin type B receptor (ETR) plays a crucial role in regulating blood pressure and humoral homeostasis, making it an important therapeutic target for related diseases. ETR activation by the ...Endothelin type B receptor (ETR) plays a crucial role in regulating blood pressure and humoral homeostasis, making it an important therapeutic target for related diseases. ETR activation by the endogenous peptide hormones endothelin (ET)-1-3 stimulates several signaling pathways, including G, G, G, G, and β-arrestin. Although the conserved NPxxY motif in transmembrane helix 7 (TM7) is important during GPCR activation, ETR possesses the lesser known NPxxL motif. In this study, we present the cryo-EM structure of the ETR-G complex, complemented by MD simulations and functional studies. These investigations reveal an unusual movement of TM7 to the intracellular side during ETR activation and the essential roles of the diverse NPxxL motif in stabilizing the active conformation of ETR and organizing the assembly of the binding pocket for the α5 helix of G protein. These findings enhance our understanding of the interactions between GPCRs and G proteins, thereby advancing the development of therapeutic strategies.
History
DepositionJan 16, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: Endothelin receptor type B
L: Endothelin-1
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
D: SCFV16


Theoretical massNumber of molelcules
Total (without water)156,6516
Polymers156,6516
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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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABC

#3: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40414.047 Da / Num. of mol.: 1 / Mutation: S47N, G203A, E245A, A326S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37671.102 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
#5: 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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Protein / Protein/peptide / Antibody , 3 types, 3 molecules RLD

#1: Protein Endothelin receptor type B / ET-B / ET-BR / Endothelin receptor non-selective type


Mass: 38808.262 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EDNRB, ETRB / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24530
#2: Protein/peptide Endothelin-1 / Preproendothelin-1 / PPET1


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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P05305
#6: Antibody SCFV16


Mass: 29398.930 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)

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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: ET-1 BOUND ETBR-GI COMPLEX / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample was monodisperse.
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: JEOL CRYO ARM 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 3.4 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.21 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1038215 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029266
ELECTRON MICROSCOPYf_angle_d0.45712555
ELECTRON MICROSCOPYf_dihedral_angle_d12.2843317
ELECTRON MICROSCOPYf_chiral_restr0.0381433
ELECTRON MICROSCOPYf_plane_restr0.0031579

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