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- PDB-8jrv: Cryo-EM structure of the glucagon receptor bound to glucagon and ... -

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Basic information

Entry
Database: PDB / ID: 8jrv
TitleCryo-EM structure of the glucagon receptor bound to glucagon and beta-arrestin 1
Components
  • Beta-arrestin 1 and single-chain fragment variable 30 (scFv30)
  • Glucagon
  • HA signal peptide,HPC4 purification tag,Glucagon receptor,C-terminal tail of Vasopressin V2 receptor
  • Nanobody 32Single-domain antibody
KeywordsMEMBRANE PROTEIN / Complex structure / glucagon receptor / beta-arrestin 1 / glucagon
Function / homology
Function and homology information


protein C (activated) / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / positive regulation of establishment of endothelial barrier / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / glucagon receptor binding / negative regulation of coagulation / : ...protein C (activated) / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / positive regulation of establishment of endothelial barrier / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / glucagon receptor binding / negative regulation of coagulation / : / regulation of glycogen metabolic process / glucagon receptor activity / hemostasis / positive regulation of systemic arterial blood pressure / telencephalon development / negative regulation of execution phase of apoptosis / negative regulation of blood coagulation / feeding behavior / positive regulation of intracellular signal transduction / response to starvation / positive regulation of calcium ion import / cellular response to glucagon stimulus / exocytosis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / peptide hormone binding / regulation of insulin secretion / endocytic vesicle / Synthesis, secretion, and deacylation of Ghrelin / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / positive regulation of gluconeogenesis / positive regulation of vasoconstriction / cellular response to hormone stimulus / protein kinase A signaling / activation of adenylate cyclase activity / Intrinsic Pathway of Fibrin Clot Formation / cellular response to starvation / hormone-mediated signaling pathway / response to nutrient / guanyl-nucleotide exchange factor activity / viral budding from plasma membrane / response to activity / positive regulation of peptidyl-threonine phosphorylation / generation of precursor metabolites and energy / response to cytokine / gluconeogenesis / Cell surface interactions at the vascular wall / peptide binding / Post-translational protein phosphorylation / clathrin-coated endocytic vesicle membrane / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Glucagon signaling in metabolic regulation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / regulation of blood pressure / Vasopressin regulates renal water homeostasis via Aquaporins / negative regulation of inflammatory response / Golgi lumen / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / blood coagulation / Cargo recognition for clathrin-mediated endocytosis / positive regulation of peptidyl-serine phosphorylation / glucose homeostasis / Clathrin-mediated endocytosis / G alpha (s) signalling events / G alpha (q) signalling events / clathrin-dependent endocytosis of virus by host cell / secretory granule lumen / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / host cell surface receptor binding / endosome / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / fusion of virus membrane with host plasma membrane / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / calcium ion binding / positive regulation of cell population proliferation / virion attachment to host cell / positive regulation of gene expression / negative regulation of apoptotic process / host cell plasma membrane / virion membrane / perinuclear region of cytoplasm / Golgi apparatus / endoplasmic reticulum / proteolysis / extracellular space / extracellular region / membrane / identical protein binding
Similarity search - Function
Vasopressin V2 receptor / GPCR, family 2, glucagon 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 / G-protein coupled receptors family 2 signature 1. ...Vasopressin V2 receptor / GPCR, family 2, glucagon 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 / G-protein coupled receptors family 2 signature 1. / Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / 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) / Coagulation Factor Xa inhibitory site / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / 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 / Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / 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. / Viral capsid/haemagglutinin protein / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / 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) / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-PIO / Pro-glucagon / Hemagglutinin / Vitamin K-dependent protein C / Vasopressin V2 receptor / Glucagon receptor
Similarity search - Component
Biological speciesInfluenza A virus
Homo sapiens (human)
Escherichia phage EcSzw-2 (virus)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsChen, K. / Zhang, C. / Lin, S. / Zhao, Q. / Wu, B.
Funding support China, 2items
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, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 16, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 23, 2023Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 6, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Sep 13, 2023Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: HA signal peptide,HPC4 purification tag,Glucagon receptor,C-terminal tail of Vasopressin V2 receptor
G: Glucagon
A: Beta-arrestin 1 and single-chain fragment variable 30 (scFv30)
H: Beta-arrestin 1 and single-chain fragment variable 30 (scFv30)
L: Beta-arrestin 1 and single-chain fragment variable 30 (scFv30)
B: Nanobody 32
hetero molecules


Theoretical massNumber of molelcules
Total (without water)279,7857
Polymers279,0396
Non-polymers7471
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein HA signal peptide,HPC4 purification tag,Glucagon receptor,C-terminal tail of Vasopressin V2 receptor / GL-R / V2R / AVPR V2 / Antidiuretic hormone receptor / Renal-type arginine vasopressin receptor


Mass: 54163.012 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus (strain A/Victoria/3/1975 H3N2), (gene. exp.) Homo sapiens (human)
Gene: HA, PROC, GCGR, AVPR2, ADHR, DIR, DIR3, V2R / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P03435, UniProt: P04070, UniProt: P47871, UniProt: P30518
#2: Protein/peptide Glucagon /


Mass: 3486.781 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01275
#3: Antibody Beta-arrestin 1 and single-chain fragment variable 30 (scFv30)


Mass: 69173.891 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#4: Antibody Nanobody 32 / Single-domain antibody


Mass: 13867.408 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia phage EcSzw-2 (virus) / Production host: Escherichia coli BL21 (bacteria)
#5: Chemical 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 / dioctanoyl l-alpha-phosphatidyl-d-myo-inositol 4,5-diphosphate


Mass: 746.566 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H49O19P3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: The glucagon receptor bound to glucagon and beta-arrestin 1
Type: COMPLEX / Entity ID: #1-#4 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 6 mg/ml / Embedding 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: SPOT SCAN
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 300738 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037879
ELECTRON MICROSCOPYf_angle_d0.69710770
ELECTRON MICROSCOPYf_dihedral_angle_d13.692650
ELECTRON MICROSCOPYf_chiral_restr0.0411261
ELECTRON MICROSCOPYf_plane_restr0.0041356

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