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- EMDB-25077: GPR56 (ADGRG1) 7TM domain bound to tethered agonist in complex wi... -

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Basic information

Entry
Database: EMDB / ID: EMD-25077
TitleGPR56 (ADGRG1) 7TM domain bound to tethered agonist in complex with G protein heterotrimer
Map dataCryo-EM composite map for GPR56 - miniG13 heterotrimer
Sample
  • Complex: GPR56 (ADGRG1) 7TM domain bound to tethered agonist in complex with mini-G13 protein
    • Protein or peptide: Isoform 2 of Adhesion G-protein coupled receptor G1
    • Protein or peptide: G protein subunit 13 (Gi2-mini-G13 chimera)
    • 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
Function / homology
Function and homology information


cerebral cortex regionalization / cerebral cortex radial glia-guided migration / protein kinase C signaling / glial limiting end-foot / negative regulation of neuron migration / hematopoietic stem cell homeostasis / layer formation in cerebral cortex / vascular endothelial growth factor production / positive regulation of neural precursor cell proliferation / extracellular matrix binding ...cerebral cortex regionalization / cerebral cortex radial glia-guided migration / protein kinase C signaling / glial limiting end-foot / negative regulation of neuron migration / hematopoietic stem cell homeostasis / layer formation in cerebral cortex / vascular endothelial growth factor production / positive regulation of neural precursor cell proliferation / extracellular matrix binding / neural precursor cell proliferation / positive regulation of Rho protein signal transduction / seminiferous tubule development / Rho protein signal transduction / collagen binding / positive regulation of cell adhesion / G protein-coupled receptor activity / brain development / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / cell migration / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / cell-cell signaling / GTPase binding / heparin binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / angiogenesis / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / cell adhesion / G protein-coupled receptor signaling pathway / membrane raft / negative regulation of cell population proliferation / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PTX/LNS-Like (PLL) domain / GPCR-Autoproteolysis-INducing (GAIN) subdomain A / PTX/LNS-Like (PLL) domain / GPCR-Autoproteolysis-INducing (GAIN) subdomain A / GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5 / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / GPS motif / GAIN-B domain profile. / G-protein-coupled receptor proteolytic site domain ...PTX/LNS-Like (PLL) domain / GPCR-Autoproteolysis-INducing (GAIN) subdomain A / PTX/LNS-Like (PLL) domain / GPCR-Autoproteolysis-INducing (GAIN) subdomain A / GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5 / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / GPS motif / GAIN-B domain profile. / G-protein-coupled receptor proteolytic site domain / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / 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 beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
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 / Adhesion G-protein coupled receptor G1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsBarros-Alvarez X / Panova O / Skiniotis G
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2022
Title: The tethered peptide activation mechanism of adhesion GPCRs.
Authors: Ximena Barros-Álvarez / Robert M Nwokonko / Alexander Vizurraga / Donna Matzov / Feng He / Makaía M Papasergi-Scott / Michael J Robertson / Ouliana Panova / Eliane Hadas Yardeni / Alpay B ...Authors: Ximena Barros-Álvarez / Robert M Nwokonko / Alexander Vizurraga / Donna Matzov / Feng He / Makaía M Papasergi-Scott / Michael J Robertson / Ouliana Panova / Eliane Hadas Yardeni / Alpay B Seven / Frank E Kwarcinski / Hongyu Su / Maria Claudia Peroto / Justin G Meyerowitz / Moran Shalev-Benami / Gregory G Tall / Georgios Skiniotis /
Abstract: Adhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell-cell and cell-extracellular matrix interactions. ...Adhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell-cell and cell-extracellular matrix interactions. Self cleavage within the aGPCR auto-proteolysis-inducing (GAIN) domain produces two protomers-N-terminal and C-terminal fragments-that remain non-covalently attached after receptors reach the cell surface. Upon dissociation of the N-terminal fragment, the C-terminus of the GAIN domain acts as a tethered agonist (TA) peptide to activate the seven-transmembrane domain with a mechanism that has been poorly understood. Here we provide cryo-electron microscopy snapshots of two distinct members of the aGPCR family, GPR56 (also known as ADGRG1) and latrophilin 3 (LPHN3 (also known as ADGRL3)). Low-resolution maps of the receptors in their N-terminal fragment-bound state indicate that the GAIN domain projects flexibly towards the extracellular space, keeping the encrypted TA peptide away from the seven-transmembrane domain. High-resolution structures of GPR56 and LPHN3 in their active, G-protein-coupled states, reveal that after dissociation of the extracellular region, the decrypted TA peptides engage the seven-transmembrane domain core with a notable conservation of interactions that also involve extracellular loop 2. TA binding stabilizes breaks in the middle of transmembrane helices 6 and 7 that facilitate aGPCR coupling and activation of heterotrimeric G proteins. Collectively, these results enable us to propose a general model for aGPCR activation.
History
DepositionOct 3, 2021-
Header (metadata) releaseApr 27, 2022-
Map releaseApr 27, 2022-
UpdateMay 11, 2022-
Current statusMay 11, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25077.png

Downloads & links

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Map

FileDownload / File: emd_25077.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM composite map for GPR56 - miniG13 heterotrimer
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.87 Å/pix.
x 360 pix.
= 312.372 Å		0.87 Å/pix.
x 360 pix.
= 312.372 Å		0.87 Å/pix.
x 360 pix.
= 312.372 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8677 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.013981534 - 3.0808938
Average (Standard dev.)0.0004912515 (±0.014758516)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 312.37198 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Local refinement of GPR56 7TM domain

Fileemd_25077_additional_1.map
AnnotationLocal refinement of GPR56 7TM domain
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Local refinement of miniG13 heterotrimer

Fileemd_25077_additional_2.map
AnnotationLocal refinement of miniG13 heterotrimer
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : GPR56 (ADGRG1) 7TM domain bound to tethered agonist in complex wi...

EntireName: GPR56 (ADGRG1) 7TM domain bound to tethered agonist in complex with mini-G13 protein
Components
  • Complex: GPR56 (ADGRG1) 7TM domain bound to tethered agonist in complex with mini-G13 protein
    • Protein or peptide: Isoform 2 of Adhesion G-protein coupled receptor G1
    • Protein or peptide: G protein subunit 13 (Gi2-mini-G13 chimera)
    • 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

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Supramolecule #1: GPR56 (ADGRG1) 7TM domain bound to tethered agonist in complex wi...

SupramoleculeName: GPR56 (ADGRG1) 7TM domain bound to tethered agonist in complex with mini-G13 protein
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)

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Macromolecule #1: Isoform 2 of Adhesion G-protein coupled receptor G1

MacromoleculeName: Isoform 2 of Adhesion G-protein coupled receptor G1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.798094 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: TYFAVLMVSS VEVDAVHKHY LSLLSYVGCV VSALACLVTI AAYLCSRRKP RDYTIKVHMN LLLAVFLLDT SFLLSEPVAL TGSEAGCRA SAIFLHFSLL TCLSWMGLEG YNLYRLVVEV FGTYVPGYLL KLSAMGWGFP IFLVTLVALV DVDNYGPIIL A VHRTPEGV ...String:
TYFAVLMVSS VEVDAVHKHY LSLLSYVGCV VSALACLVTI AAYLCSRRKP RDYTIKVHMN LLLAVFLLDT SFLLSEPVAL TGSEAGCRA SAIFLHFSLL TCLSWMGLEG YNLYRLVVEV FGTYVPGYLL KLSAMGWGFP IFLVTLVALV DVDNYGPIIL A VHRTPEGV IYPSMCWIRD SLVSYITNLG LFSLVFLFNM AMLATMVVQI LRLRPHTQKW SHVLTLLGLS LVLGLPWALI FF SFASGTF QLVVLYLFSI ITSFQGFLIF IWYWSMRLQA RGGPSPLKSN SDSARLPISS GSTSSSRIGS LEVLFQ

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Macromolecule #2: G protein subunit 13 (Gi2-mini-G13 chimera)

MacromoleculeName: G protein subunit 13 (Gi2-mini-G13 chimera) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.5744 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSTVSAEDK AAAERSKEID KCLSREKTYV KRLVKILLLG ADNSGKSTFL KQMRIIHGGS GGSGGTKGIH EYDFEIKNVP FKMVDVGGQ RSERKRWFEC FDSVTSILFL VDSSDFNRLT ESLNDFETIV NNRVFSNVSI ILFLNKTDLL EEKVQIVSIK D YFLEFEGD ...String:
MGSTVSAEDK AAAERSKEID KCLSREKTYV KRLVKILLLG ADNSGKSTFL KQMRIIHGGS GGSGGTKGIH EYDFEIKNVP FKMVDVGGQ RSERKRWFEC FDSVTSILFL VDSSDFNRLT ESLNDFETIV NNRVFSNVSI ILFLNKTDLL EEKVQIVSIK D YFLEFEGD PHCLRDVQKF LVECFRNKRR DQQQKPLYHH FTTAINTENA RLIFRDVKDT ILHDNLKQLM LQ

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.41693 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String:
MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN

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Macromolecule #4: 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: 4 / 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

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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

Concentration7.5 mg/mL
BufferpH: 7.5
GridModel: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK II

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.07 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated magnification: 55000 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 3.2)
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2) / Number images used: 541279
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. 3.2)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. 3.2)
FSC plot (resolution estimation)

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