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- EMDB-36607: Cryo-EM structure of the glucagon receptor bound to glucagon and ... -

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Entry
Database: EMDB / ID: EMD-36607
TitleCryo-EM structure of the glucagon receptor bound to glucagon and beta-arrestin 1
Map data
Sample
  • Complex: The glucagon receptor bound to glucagon and beta-arrestin 1
    • Protein or peptide: HA signal peptide,HPC4 purification tag,Glucagon receptor,C-terminal tail of Vasopressin V2 receptor
    • Protein or peptide: Glucagon
    • Protein or peptide: Beta-arrestin 1 and single-chain fragment variable 30 (scFv30)
    • Protein or peptide: Nanobody 32
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
KeywordsComplex structure / glucagon receptor / beta-arrestin 1 / glucagon / MEMBRANE PROTEIN
Function / homology
Function and homology information


activated protein C (thrombin-activated peptidase) / positive regulation of establishment of endothelial barrier / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / negative regulation of coagulation / glucagon receptor binding / regulation of glycogen metabolic process ...activated protein C (thrombin-activated peptidase) / positive regulation of establishment of endothelial barrier / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / negative regulation of coagulation / glucagon receptor binding / regulation of glycogen metabolic process / hemostasis / glucagon receptor activity / telencephalon development / protein kinase A signaling / negative regulation of execution phase of apoptosis / feeding behavior / response to starvation / positive regulation of calcium ion import / positive regulation of systemic arterial blood pressure / peptide hormone binding / positive regulation of intracellular signal transduction / negative regulation of blood coagulation / Synthesis, secretion, and deacylation of Ghrelin / endocytic vesicle / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / positive regulation of insulin secretion involved in cellular response to glucose stimulus / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / positive regulation of vasoconstriction / activation of adenylate cyclase activity / cellular response to hormone stimulus / Intrinsic Pathway of Fibrin Clot Formation / response to cytokine / positive regulation of gluconeogenesis / response to nutrient / cellular response to glucagon stimulus / regulation of insulin secretion / guanyl-nucleotide exchange factor activity / viral budding from plasma membrane / cellular response to starvation / response to activity / gluconeogenesis / Cell surface interactions at the vascular wall / generation of precursor metabolites and energy / Post-translational protein phosphorylation / clathrin-coated endocytic vesicle membrane / hormone activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / regulation of blood pressure / negative regulation of inflammatory response / Golgi lumen / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Glucagon signaling in metabolic regulation / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / blood coagulation / Vasopressin regulates renal water homeostasis via Aquaporins / Cargo recognition for clathrin-mediated endocytosis / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Clathrin-mediated endocytosis / glucose homeostasis / secretory granule lumen / G alpha (s) signalling events / clathrin-dependent endocytosis of virus by host cell / G alpha (q) signalling events / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / endosome / host cell surface receptor binding / G protein-coupled receptor signaling pathway / receptor ligand activity / endoplasmic reticulum lumen / signaling receptor binding / negative regulation of cell population proliferation / serine-type endopeptidase activity / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / positive regulation of cell population proliferation / viral envelope / calcium ion binding / positive regulation of gene expression / negative regulation of apoptotic process / virion attachment to host cell / perinuclear region of cytoplasm / host cell plasma membrane / virion membrane / endoplasmic reticulum / Golgi apparatus / proteolysis / extracellular space / extracellular region / identical protein binding / membrane / plasma membrane
Similarity search - Function
GPCR, family 2, glucagon receptor / Vasopressin V2 receptor / Vasopressin receptor / Glucagon / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / GPCR, family 2, glucagon-like peptide-1/glucagon receptor / Peptidase S1A, coagulation factor VII/IX/X/C/Z ...GPCR, family 2, glucagon receptor / Vasopressin V2 receptor / Vasopressin receptor / Glucagon / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / GPCR, family 2, glucagon-like peptide-1/glucagon receptor / Peptidase S1A, coagulation factor VII/IX/X/C/Z / : / Coagulation factor-like, Gla domain superfamily / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / Coagulation Factor Xa inhibitory site / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Vitamin K-dependent carboxylation domain. / Gla domain profile. / Domain containing Gla (gamma-carboxyglutamate) residues. / Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 1. / EGF-like domain signature 2. / EGF-like domain / G-protein coupled receptors family 1 signature. / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Pro-glucagon / Hemagglutinin / Vitamin K-dependent protein C / Vasopressin V2 receptor / Glucagon receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / Escherichia phage EcSzw-2 (virus)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsChen K / Zhang C / Lin S / Zhao Q / Wu B
Funding support China, 2 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)82121005 China
CitationJournal: Nature / Year: 2023
Title: Tail engagement of arrestin at the glucagon receptor.
Authors: Kun Chen / Chenhui Zhang / Shuling Lin / Xinyu Yan / Heng Cai / Cuiying Yi / Limin Ma / Xiaojing Chu / Yuchen Liu / Ya Zhu / Shuo Han / Qiang Zhao / Beili Wu /
Abstract: Arrestins have pivotal roles in regulating G protein-coupled receptor (GPCR) signalling by desensitizing G protein activation and mediating receptor internalization. It has been proposed that the ...Arrestins have pivotal roles in regulating G protein-coupled receptor (GPCR) signalling by desensitizing G protein activation and mediating receptor internalization. It has been proposed that the arrestin binds to the receptor in two different conformations, 'tail' and 'core', which were suggested to govern distinct processes of receptor signalling and trafficking. However, little structural information is available for the tail engagement of the arrestins. Here we report two structures of the glucagon receptor (GCGR) bound to β-arrestin 1 (βarr1) in glucagon-bound and ligand-free states. These structures reveal a receptor tail-engaged binding mode of βarr1 with many unique features, to our knowledge, not previously observed. Helix VIII, instead of the receptor core, has a major role in accommodating βarr1 by forming extensive interactions with the central crest of βarr1. The tail-binding pose is further defined by a close proximity between the βarr1 C-edge and the receptor helical bundle, and stabilized by a phosphoinositide derivative that bridges βarr1 with helices I and VIII of GCGR. Lacking any contact with the arrestin, the receptor core is in an inactive state and loosely binds to glucagon. Further functional studies suggest that the tail conformation of GCGR-βarr governs βarr recruitment at the plasma membrane and endocytosis of GCGR, and provides a molecular basis for the receptor forming a super-complex simultaneously with G protein and βarr to promote sustained signalling within endosomes. These findings extend our knowledge about the arrestin-mediated modulation of GPCR functionalities.
History
DepositionJun 17, 2023-
Header (metadata) releaseAug 16, 2023-
Map releaseAug 16, 2023-
UpdateJul 16, 2025-
Current statusJul 16, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36607.png

Downloads & links

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Map

FileDownload / File: emd_36607.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 274.176 Å		1.07 Å/pix.
x 256 pix.
= 274.176 Å		1.07 Å/pix.
x 256 pix.
= 274.176 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.071 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-0.0011917887 - 2.8401237
Average (Standard dev.)0.0061923782 (±0.059086576)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 274.176 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36607_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_36607_half_map_2.map
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Sample components

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Entire : The glucagon receptor bound to glucagon and beta-arrestin 1

EntireName: The glucagon receptor bound to glucagon and beta-arrestin 1
Components
  • Complex: The glucagon receptor bound to glucagon and beta-arrestin 1
    • Protein or peptide: HA signal peptide,HPC4 purification tag,Glucagon receptor,C-terminal tail of Vasopressin V2 receptor
    • Protein or peptide: Glucagon
    • Protein or peptide: Beta-arrestin 1 and single-chain fragment variable 30 (scFv30)
    • Protein or peptide: Nanobody 32
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

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Supramolecule #1: The glucagon receptor bound to glucagon and beta-arrestin 1

SupramoleculeName: The glucagon receptor bound to glucagon and beta-arrestin 1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: HA signal peptide,HPC4 purification tag,Glucagon receptor,C-termi...

MacromoleculeName: HA signal peptide,HPC4 purification tag,Glucagon receptor,C-terminal tail of Vasopressin V2 receptor
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.163012 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFAGAPE DQVDPRLIDG KGSGSAGSAG SQVMDFLFEK WKLYGDQCHH NLSLLPPPTE LVCNRTFDKY SCWPDTPAN TTANISCPWY LPWHHKVQHR FVFKRCGPDG QWVRGPRGQP WRDASQCQMD GEEIEVQKEV AKMYSSFQVM Y TVGYSLSL ...String:
MKTIIALSYI FCLVFAGAPE DQVDPRLIDG KGSGSAGSAG SQVMDFLFEK WKLYGDQCHH NLSLLPPPTE LVCNRTFDKY SCWPDTPAN TTANISCPWY LPWHHKVQHR FVFKRCGPDG QWVRGPRGQP WRDASQCQMD GEEIEVQKEV AKMYSSFQVM Y TVGYSLSL GALLLALAIL GGLSKLHCTR NAIHANLFAS FVLKASSVLV IDGLLRTRYS QKIGDDLSVS TWLSDGAVAG CR VAAVFMQ YGIVANYCWL LVEGLYLHNL LGLATLPERS FFSLYLGIGW GAPMLFVVPW AVVKCLFENV QCWTSNDNMG FWW ILRFPV FLAILINFFI FVRIVQLLVA KLRARQMHHT DYKFRLAKST LTLIPLLGVH EVVFAFVTDE HAQGTLRSAK LFFD LFLSS FQGLLVAVLY CFLNKEVQSE LRRRWHRWRL GKVLWEERNT SNARGRTPPS LGPQDE(SEP)CT(TPO) A(SEP) (SEP)(SEP)LAKDT SS

UniProtKB: Hemagglutinin, Vitamin K-dependent protein C, Glucagon receptor, Vasopressin V2 receptor

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Macromolecule #2: Glucagon

MacromoleculeName: Glucagon / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.486781 KDa
SequenceString:
HSQGTFTSDY SKYLDSRRAQ DFVQWLMNT

UniProtKB: Pro-glucagon

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Macromolecule #3: Beta-arrestin 1 and single-chain fragment variable 30 (scFv30)

MacromoleculeName: Beta-arrestin 1 and single-chain fragment variable 30 (scFv30)
type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 69.173891 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVEPVDGV VLVDPEYLKE RRVYVTLTAA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPSSVTL QPGPEDTGKA IGVDYEVKAF VAENLEEKIH K RNSVRLVI ...String:
MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVEPVDGV VLVDPEYLKE RRVYVTLTAA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPSSVTL QPGPEDTGKA IGVDYEVKAF VAENLEEKIH K RNSVRLVI EKVQYAPERP GPQPTAETTR QFLMSDKPLH LEASLDKEIY YHGEPISVNV HVTNNTNKTV KKIKISVRQY AD IVLFNTA QYKVPVAMEE ADDTVAPSST FSKVYTLTPF LANNREKRGL ALDGKLKHED TNLASSTLLR EGANREILGI IVS YKVKVK LVVSRGGLLG DLASSDVAVE LPFTLMHPKP KEEPPHREVP EHETPVDTNL SDIQMTQSPS SLSASVGDRV TITC RASQS VSSAVAWYQQ KPGKAPKLLI YSASSLYSGV PSRFSGSRSG TDFTLTISSL QPEDFATYYC QQYKYVPVTF GQGTK VEIK GTTAASGSSG GSSSGAEVQL VESGGGLVQP GGSLRLSCAA SGFNVYSSSI HWVRQAPGKG LEWVASISSY YGYTYY ADS VKGRFTISAD TSKNTAYLQM NSLRAEDTAV YYCARSRQFW YSGLDYWGQG TLVTVSSAHH HHHH

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Macromolecule #4: Nanobody 32

MacromoleculeName: Nanobody 32 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Escherichia phage EcSzw-2 (virus)
Molecular weightTheoretical: 13.867408 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString:
MAQVQLQESG GGLVQAGGSL RLSCVVSGFF FDTVTMAWYR RAPGKHRELV ASATAGGTTT YADSVKDRFT ISRDNAKNTV YLQMNSLKP EDTAVYYCNT FVRSLSWGQG TQVTVSSHHH HHHEPEA

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Macromolecule #5: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(o...

MacromoleculeName: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
type: ligand / ID: 5 / Number of copies: 1 / Formula: PIO
Molecular weightTheoretical: 746.566 Da
Chemical component information

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

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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

Concentration6 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 300738
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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