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- PDB-9vos: Cryo-EM Structure of GPR158 in Complex with RGS7-Gbeta5 and Nanob... -

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Basic information

Entry
Database: PDB / ID: 9vos
TitleCryo-EM Structure of GPR158 in Complex with RGS7-Gbeta5 and Nanobody Nb20
Components
  • Guanine nucleotide-binding protein subunit beta-5
  • Isoform 2 of Regulator of G-protein signaling 7
  • Metabotropic glycine receptor
  • Nb20
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / orphan receptor / nanobody / RGS proteins / signalling receptor / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


G protein-coupled glycine receptor activity / dendrite terminus / Inactivation, recovery and regulation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Prostacyclin signalling through prostacyclin receptor / G alpha (z) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 ...G protein-coupled glycine receptor activity / dendrite terminus / Inactivation, recovery and regulation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Prostacyclin signalling through prostacyclin receptor / G alpha (z) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thromboxane signalling through TP receptor / G beta:gamma signalling through BTK / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / light adaption / dark adaptation / G-protein gamma-subunit binding / G alpha (s) signalling events / Ca2+ pathway / G-protein activation / Extra-nuclear estrogen signaling / G alpha (12/13) signalling events / G alpha (q) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / GPER1 signaling / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / positive regulation of neurotransmitter secretion / ADP signalling through P2Y purinoceptor 1 / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cell tip / G alpha (i) signalling events / regulation of G protein-coupled receptor signaling pathway / GTPase activating protein binding / G protein-coupled dopamine receptor signaling pathway / negative regulation of G protein-coupled receptor signaling pathway / regulation of synapse organization / parallel fiber to Purkinje cell synapse / regulation of postsynaptic membrane potential / positive regulation of GTPase activity / photoreceptor outer segment / G-protein alpha-subunit binding / photoreceptor inner segment / protein localization to plasma membrane / GTPase activator activity / brain development / postsynaptic density membrane / cognition / enzyme activator activity / transmembrane signaling receptor activity / myelin sheath / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / heterotrimeric G-protein complex / G-protein beta-subunit binding / presynapse / protein-folding chaperone binding / signaling receptor complex adaptor activity / cell body / presynaptic membrane / G alpha (i) signalling events / postsynaptic membrane / intracellular signal transduction / neuron projection / G protein-coupled receptor signaling pathway / GTPase activity / synapse / dendrite / glutamatergic synapse / protein-containing complex / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Regulator of G-protein signalling, DHEX domain / : / : / Regulator of G-protein signalling DHEX domain / G-protein coupled receptor 158/179 / : / GPR158/179 extracellular domain / Regulator of G protein signaling domain / Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. ...Regulator of G-protein signalling, DHEX domain / : / : / Regulator of G-protein signalling DHEX domain / G-protein coupled receptor 158/179 / : / GPR158/179 extracellular domain / Regulator of G protein signaling domain / Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS, subdomain 2 / RGS domain superfamily / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / 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 / Winged helix DNA-binding domain superfamily / 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 / Winged helix-like DNA-binding domain superfamily / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
CHOLESTEROL / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / Chem-PII / Regulator of G-protein signaling 7 / Guanine nucleotide-binding protein subunit beta-5 / Metabotropic glycine receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsLaboute, T. / Zucca, S. / Sial, M. / Sharma, M. / Brunori, G. / Singh, S. / Singh, A. / Martemyanov, K.
Funding support United States, India, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Eye Institute (NIH/NEI)MH105482 United States
National Institutes of Health/National Eye Institute (NIH/NEI)EY034339 United States
Indian Council of Medical ResearchNeuro/2022-NCD-I India
Department of Biotechnology (DBT, India)Neuro/2022-NCD-I India
CitationJournal: Nat Commun / Year: 2026
Title: Targeting mGlyR with nanobodies for depression.
Authors: Thibaut Laboute / Stefano Zucca / Omar K Sial / Mansi Sharma / Gloria Brunori / Shikha Singh / K V Nageswar / Haiyong Peng / Christoph Rader / Jérôme Aj Becker / Julie Le Merrer / Appu K ...Authors: Thibaut Laboute / Stefano Zucca / Omar K Sial / Mansi Sharma / Gloria Brunori / Shikha Singh / K V Nageswar / Haiyong Peng / Christoph Rader / Jérôme Aj Becker / Julie Le Merrer / Appu K Singh / Kirill A Martemyanov /
Abstract: Development of therapies for neuropsychiatric conditions is one of the greatest challenges of modern medicine. Common limitations of traditional small molecule drugs include poor efficacy, off-target ...Development of therapies for neuropsychiatric conditions is one of the greatest challenges of modern medicine. Common limitations of traditional small molecule drugs include poor efficacy, off-target side effects and difficult druggability of many targets. In this study, we report a different approach deploying small engineered single domain antibodies, known as nanobodies, for the treatment of depression, a prevalent neuropsychiatric condition. We develop highly selective nanobodies for a recently discovered glycine receptor mGlyR crucially linked to pathophysiology of depression. Using a mouse model of stress-induced depression, we show that non-invasive intranasal delivery of nanobody produces rapid and lasting anti-depressant effect. We solve an atomic structure of mGlyR bound to nanobody and use a variety of cell-based approaches to reveal the mechanism of mGlyR modulation and its impact on neural circuitry. These findings support development of biologics for the treatment of intractable brain disorders.
History
DepositionJul 2, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 22, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Metabotropic glycine receptor
A: Metabotropic glycine receptor
C: Isoform 2 of Regulator of G-protein signaling 7
D: Guanine nucleotide-binding protein subunit beta-5
H: Nb20
I: Nb20
hetero molecules


Theoretical massNumber of molelcules
Total (without water)313,56430
Polymers303,4896
Non-polymers10,07524
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 4 molecules BACD

#1: Protein Metabotropic glycine receptor / mGlyR / G-protein coupled receptor 158


Mass: 88251.633 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPR158, KIAA1136 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q5T848
#2: Protein Isoform 2 of Regulator of G-protein signaling 7 / RGS7


Mass: 54761.859 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RGS7 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P49802
#3: Protein Guanine nucleotide-binding protein subunit beta-5 / Gbeta5 / Transducin beta chain 5


Mass: 38778.602 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Gnb5 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P62881

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Antibody , 1 types, 2 molecules HI

#4: Antibody Nb20


Mass: 16722.469 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama)
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)

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Non-polymers , 3 types, 24 molecules

#5: Chemical...
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 22 / Source method: obtained synthetically / Formula: C27H46O
#6: Chemical ChemComp-PEE / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE


Mass: 744.034 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H78NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: DOPE, phospholipid*YM
#7: Chemical ChemComp-PII / 2-[(HYDROXY{[(2R,3R,5S,6R)-2,3,4,5,6-PENTAHYDROXYCYCLOHEXYL]OXY}PHOSPHORYL)OXY]-1-[(PALMITOYLOXY)METHYL]ETHYL HEPTADECANOATE


Mass: 825.059 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H81O13P / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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

Component
IDNameTypeEntity IDParent-IDSource
1GPR158 complexed with Nb20COMPLEX#1-#40RECOMBINANT
2GRP158-RGS7COMPLEX#1-#21RECOMBINANT
3Gbeta5COMPLEX#31RECOMBINANT
4nanobodyCOMPLEX#41RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Mus musculus (house mouse)10090
44Lama glama (llama)9844
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)866768
Buffer solutionpH: 8
SpecimenConc.: 0.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 48 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 4 / Num. of real images: 40

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 91859 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL

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