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- EMDB-38740: Cryo-EM structure of ET-1 bound ETBR-DNGI complex -

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Entry
Database: EMDB / ID: EMD-38740
TitleCryo-EM structure of ET-1 bound ETBR-DNGI complex
Map data
Sample
  • Complex: ET-1 BOUND ETBR-GI COMPLEX
    • Protein or peptide: Endothelin receptor type B
    • Protein or peptide: Endothelin-1
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: SCFV16
KeywordsENDOTHELIN / RECEPTOR / Gi / COMPLEX / MEMBRANE PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.21 Å
AuthorsTani K / Maki-Yonekura S / Kanno R / Negami T / Hamaguchi T / Hall M / Mizoguchi A / Humbel BM / Terada T / Yonekura K / Doi T
Funding support Japan, 3 items
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, 2024-
Header (metadata) releaseOct 2, 2024-
Map releaseOct 2, 2024-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38740.png

Downloads & links

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Map

FileDownload / File: emd_38740.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.19 Å/pix.
x 192 pix.
= 228.48 Å		1.19 Å/pix.
x 192 pix.
= 228.48 Å		1.19 Å/pix.
x 192 pix.
= 228.48 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.19 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015
Minimum - Maximum-0.148493 - 0.21696313
Average (Standard dev.)0.000054176497 (±0.004675841)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 228.48001 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_38740_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_38740_half_map_2.map
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Sample components

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Entire : ET-1 BOUND ETBR-GI COMPLEX

EntireName: ET-1 BOUND ETBR-GI COMPLEX
Components
  • Complex: ET-1 BOUND ETBR-GI COMPLEX
    • Protein or peptide: Endothelin receptor type B
    • Protein or peptide: Endothelin-1
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: SCFV16

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Supramolecule #1: ET-1 BOUND ETBR-GI COMPLEX

SupramoleculeName: ET-1 BOUND ETBR-GI COMPLEX / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Endothelin receptor type B

MacromoleculeName: Endothelin receptor type B / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.808262 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: PGGGLAPAEV PKGDRTAGSP PRTISPPPCQ GPIEIKETFK YINTVVSCLV FVLGIIGNST LLYIIYKNKC MRNGPNILIA SLALGDLLH IVIDIPINVY KLLAEDWPFG AEMCKLVPFI QKASVGITVL SLCALSIDRY RAVASWSRIK GIGVPKWTAV E IVLIWVVS ...String:
PGGGLAPAEV PKGDRTAGSP PRTISPPPCQ GPIEIKETFK YINTVVSCLV FVLGIIGNST LLYIIYKNKC MRNGPNILIA SLALGDLLH IVIDIPINVY KLLAEDWPFG AEMCKLVPFI QKASVGITVL SLCALSIDRY RAVASWSRIK GIGVPKWTAV E IVLIWVVS VVLAVPEAIG FDIITMDYKG SYLRICLLHP VQKTAFMQFY KTAKDWWLFS FYFCLPLAIT AFFYTLMTCE ML RKKSGMQ IALNDHLKQR REVAKTVFCL VLVFALCWLP LHLSRILKLT LYNQNDPNRC ELLSFLLVLD YIGINMASLN SCI NPIALY LVSKRFKNAF KSALCCWAQS

UniProtKB: Endothelin receptor type B

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Macromolecule #2: Endothelin-1

MacromoleculeName: Endothelin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.497951 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
CSCSSLMDKE CVYFCHLDII W

UniProtKB: Endothelin-1

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Macromolecule #3: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.414047 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHASM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.671102 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT ...String:
PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DASAKLWDVR EGMCRQTFTG HESDINAICF FP NGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLLAGYDDFN CNVWDALKAD RAGVLAGHDN RVS CLGVTD DGMAVATGSW DSFLKIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #6: SCFV16

MacromoleculeName: SCFV16 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 29.39893 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MVSAIVLYVL LAAAAHSAFA DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFT ISRDDPKNTL FLQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV M TQATSSVP ...String:
MVSAIVLYVL LAAAAHSAFA DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFT ISRDDPKNTL FLQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV M TQATSSVP VTPGESVSIS CRSSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LE AEDVGVY YCMQHLEYPL TFGAGTKLEL KGSLEVLFQG

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE
DetailsThis sample was monodisperse.

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Electron microscopy

MicroscopeJEOL CRYO ARM 300
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 3.4 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.5 µm / Nominal defocus min: 0.5 µm

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.21 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1038215
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

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

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