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- EMDB-9377: Structure of a GPCR-G protein-beta-arrestin mega-complex -

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Entry
Database: EMDB / ID: EMD-9377
TitleStructure of a GPCR-G protein-beta-arrestin mega-complex
Map dataGPCR-G protein-beta-arrestin mega-complex
Sample
  • Complex: GPCR-G protein-beta-arrestin mega-complex
Function / homology
Function and homology information


TGFBR3 regulates TGF-beta signaling / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / MAP2K and MAPK activation / Activation of SMO / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / Golgi Associated Vesicle Biogenesis / Lysosome Vesicle Biogenesis ...TGFBR3 regulates TGF-beta signaling / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / MAP2K and MAPK activation / Activation of SMO / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / Golgi Associated Vesicle Biogenesis / Lysosome Vesicle Biogenesis / AP-2 adaptor complex binding / Ub-specific processing proteases / clathrin coat of coated pit / clathrin heavy chain binding / Cargo recognition for clathrin-mediated endocytosis / hemostasis / desensitization of G protein-coupled receptor signaling pathway / telencephalon development / Clathrin-mediated endocytosis / clathrin-dependent endocytosis / G protein-coupled receptor internalization / acetylcholine receptor binding / inositol hexakisphosphate binding / positive regulation of mini excitatory postsynaptic potential / beta2-adrenergic receptor activity / AMPA selective glutamate receptor signaling pathway / norepinephrine binding / positive regulation of autophagosome maturation / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / heat generation / Adrenoceptors / activation of transmembrane receptor protein tyrosine kinase activity / negative regulation of smooth muscle contraction / positive regulation of lipophagy / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (s) signalling events / negative regulation of G protein-coupled receptor signaling pathway / negative regulation of multicellular organism growth / clathrin binding / adrenergic receptor signaling pathway / response to psychosocial stress / endosome to lysosome transport / diet induced thermogenesis / neuronal dense core vesicle / small molecule binding / positive regulation of systemic arterial blood pressure / pseudopodium / phosphatidylinositol-3,4,5-trisphosphate binding / positive regulation of intracellular signal transduction / positive regulation of cAMP/PKA signal transduction / positive regulation of receptor internalization / adenylate cyclase binding / PKA activation in glucagon signalling / smooth muscle contraction / endocytic vesicle / hair follicle placode formation / negative regulation of Notch signaling pathway / developmental growth / D1 dopamine receptor binding / bone resorption / positive regulation of bone mineralization / potassium channel regulator activity / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / brown fat cell differentiation / renal water homeostasis / intercellular bridge / cellular response to hormone stimulus / Hedgehog 'off' state / viral release from host cell by cytolysis / regulation of sodium ion transport / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / positive regulation of vasoconstriction / peptidoglycan catabolic process / response to cytokine / regulation of insulin secretion / cellular response to glucagon stimulus / receptor-mediated endocytosis / adenylate cyclase activator activity / response to cold / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / G protein-coupled receptor binding / clathrin-coated endocytic vesicle membrane / bone development / receptor internalization / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / platelet aggregation / Olfactory Signaling Pathway / cognition / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels
Similarity search - Function
Vasopressin V2 receptor / Vasopressin receptor / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain ...Vasopressin V2 receptor / Vasopressin receptor / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin-like, C-terminal / Beta 2 adrenoceptor / Adrenoceptor family / G-protein alpha subunit, group S / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / Lysozyme-like domain superfamily / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Immunoglobulin E-set / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / 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
Endolysin / Beta-2 adrenergic receptor / Beta-arrestin-1 / Vasopressin V2 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 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.84 Å
AuthorsNguyen AH / Thomsen ARB / Cahill TJ / des Georges A / Lefkowitz RJ
Funding support United States, 2 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)2R01-HL016037-47 United States
CitationJournal: Nat Struct Mol Biol / Year: 2019
Title: Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex.
Authors: Anthony H Nguyen / Alex R B Thomsen / Thomas J Cahill / Rick Huang / Li-Yin Huang / Tara Marcink / Oliver B Clarke / Søren Heissel / Ali Masoudi / Danya Ben-Hail / Fadi Samaan / Venkata P ...Authors: Anthony H Nguyen / Alex R B Thomsen / Thomas J Cahill / Rick Huang / Li-Yin Huang / Tara Marcink / Oliver B Clarke / Søren Heissel / Ali Masoudi / Danya Ben-Hail / Fadi Samaan / Venkata P Dandey / Yong Zi Tan / Chuan Hong / Jacob P Mahoney / Sarah Triest / John Little / Xin Chen / Roger Sunahara / Jan Steyaert / Henrik Molina / Zhiheng Yu / Amedee des Georges / Robert J Lefkowitz /
Abstract: Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by β-arrestin (β-arr). However, some GPCRs continue to ...Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by β-arrestin (β-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR-G protein-β-arr 'megaplex'. Nevertheless, the molecular architecture of the megaplex remains unknown. Here, we present its cryo-electron microscopy structure, which shows simultaneous engagement of human G protein and bovine β-arr to the core and phosphorylated tail, respectively, of a single active human chimeric β-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (βVR). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and β-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling.
History
DepositionDec 26, 2018-
Header (metadata) releaseFeb 20, 2019-
Map releaseNov 20, 2019-
UpdateDec 18, 2019-
Current statusDec 18, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.08
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.08
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9377.png

Downloads & links

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Map

FileDownload / File: emd_9377.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationGPCR-G protein-beta-arrestin mega-complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 240 pix.
= 249.6 Å		1.04 Å/pix.
x 240 pix.
= 249.6 Å		1.04 Å/pix.
x 240 pix.
= 249.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08 / Movie #1: 0.08
Minimum - Maximum-0.097968325 - 0.37767392
Average (Standard dev.)0.0014590815 (±0.018979814)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 249.59999 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z249.600249.600249.600
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.0980.3780.001

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Supplemental data

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Sample components

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Entire : GPCR-G protein-beta-arrestin mega-complex

EntireName: GPCR-G protein-beta-arrestin mega-complex
Components
  • Complex: GPCR-G protein-beta-arrestin mega-complex

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Supramolecule #1: GPCR-G protein-beta-arrestin mega-complex

SupramoleculeName: GPCR-G protein-beta-arrestin mega-complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)

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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

BufferpH: 7.4
GridDetails: unidentified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 104.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.84 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 317529
Initial angle assignmentType: OTHER / Software - Name: cryoSPARC
Final angle assignmentType: OTHER / Software - Name: cryoSPARC

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