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- PDB-9nb9: Viral protein DP71L in complex with phosphorylated eIF2alpha (NTD... -

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Basic information

Entry
Database: PDB / ID: 9nb9
TitleViral protein DP71L in complex with phosphorylated eIF2alpha (NTD) and protein phosphatase 1A (D64A), stabilized by G-actin/DNAseI
Components
  • Actin, alpha skeletal muscle
  • Deoxyribonuclease-1
  • Eukaryotic translation initiation factor 2 subunit 1
  • Protein DP71L
  • Serine/threonine-protein phosphatase PP1-alpha catalytic subunit
KeywordsTRANSLATION / Phosphatase / complex / ISR
Function / homology
Function and homology information


regulation of macromolecule metabolic process / regulation of neutrophil mediated cytotoxicity / regulation of primary metabolic process / zymogen granule / regulation of acute inflammatory response / protein serine/threonine phosphatase inhibitor activity / regulation of glycogen catabolic process / translation initiation ternary complex / regulation of translation in response to endoplasmic reticulum stress / glial limiting end-foot ...regulation of macromolecule metabolic process / regulation of neutrophil mediated cytotoxicity / regulation of primary metabolic process / zymogen granule / regulation of acute inflammatory response / protein serine/threonine phosphatase inhibitor activity / regulation of glycogen catabolic process / translation initiation ternary complex / regulation of translation in response to endoplasmic reticulum stress / glial limiting end-foot / HRI-mediated signaling / response to kainic acid / deoxyribonuclease I / Cellular response to mitochondrial stress / response to manganese-induced endoplasmic reticulum stress / positive regulation of type B pancreatic cell apoptotic process / PTW/PP1 phosphatase complex / Response of EIF2AK1 (HRI) to heme deficiency / Recycling of eIF2:GDP / negative regulation of translational initiation in response to stress / PERK-mediated unfolded protein response / protein phosphatase type 1 complex / PERK regulates gene expression / glycogen granule / eukaryotic translation initiation factor 2 complex / deoxyribonuclease I activity / symbiont-mediated suppression of host translation initiation / protein phosphatase 1 binding / neutrophil activation involved in immune response / cadherin binding involved in cell-cell adhesion / regulation of translational initiation in response to stress / eukaryotic 48S preinitiation complex / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / DNA catabolic process / regulation of canonical Wnt signaling pathway / Formation of the ternary complex, and subsequently, the 43S complex / cytoskeletal motor activator activity / dephosphorylation / histone H2AXS139 phosphatase activity / RNA polymerase II CTD heptapeptide repeat Y1 phosphatase activity / RNA polymerase II CTD heptapeptide repeat T4 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity / MAP kinase serine/threonine phosphatase activity / calmodulin-dependent protein phosphatase activity / myosin phosphatase activity / branching morphogenesis of an epithelial tube / glycogen metabolic process / Ribosomal scanning and start codon recognition / protein serine/threonine phosphatase activity / myosin heavy chain binding / protein-serine/threonine phosphatase / Translation initiation complex formation / tropomyosin binding / Triglyceride catabolism / entrainment of circadian clock by photoperiod / Maturation of hRSV A proteins / troponin I binding / filamentous actin / mesenchyme migration / phosphatase activity / actin filament bundle / telomere maintenance in response to DNA damage / actin filament bundle assembly / phosphoprotein phosphatase activity / skeletal muscle myofibril / striated muscle thin filament / skeletal muscle thin filament assembly / actin monomer binding / Response of EIF2AK4 (GCN2) to amino acid deficiency / DARPP-32 events / transition metal ion binding / GTP hydrolysis and joining of the 60S ribosomal subunit / L13a-mediated translational silencing of Ceruloplasmin expression / positive regulation of glycogen biosynthetic process / ribonucleoprotein complex binding / stress fiber / mitophagy / skeletal muscle fiber development / protein dephosphorylation / titin binding / actin filament polymerization / translation initiation factor activity / stress granule assembly / cellular response to amino acid starvation / response to endoplasmic reticulum stress / Downregulation of TGF-beta receptor signaling / adherens junction / filopodium / actin filament / translational initiation / lung development / circadian regulation of gene expression / response to lead ion / regulation of circadian rhythm / PKR-mediated signaling / ABC-family proteins mediated transport / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / cytoplasmic stress granule
Similarity search - Function
Protein phosphatase 1, regulatory subunit 15A/B, C-terminal / : / Phosphatase-1 catalytic subunit binding region / Deoxyribonuclease I / Deoxyribonuclease I, active site / Deoxyribonuclease I, conservied site / Deoxyribonuclease I signature 2. / Deoxyribonuclease I signature 1. / deoxyribonuclease I / Serine-threonine protein phosphatase, N-terminal ...Protein phosphatase 1, regulatory subunit 15A/B, C-terminal / : / Phosphatase-1 catalytic subunit binding region / Deoxyribonuclease I / Deoxyribonuclease I, active site / Deoxyribonuclease I, conservied site / Deoxyribonuclease I signature 2. / Deoxyribonuclease I signature 1. / deoxyribonuclease I / Serine-threonine protein phosphatase, N-terminal / : / Serine-threonine protein phosphatase N-terminal domain / Translation initiation factor 2, alpha subunit / Translation initiation factor 2, alpha subunit, middle domain superfamily / Translation initiation factor 2, alpha subunit, C-terminal / IF2a, S1-like domain / Eukaryotic translation initiation factor 2 alpha subunit / Serine/threonine specific protein phosphatases signature. / Protein phosphatase 2A homologues, catalytic domain. / Serine/threonine-specific protein phosphatase/bis(5-nucleosyl)-tetraphosphatase / Endonuclease/exonuclease/phosphatase / Endonuclease/Exonuclease/phosphatase family / Endonuclease/exonuclease/phosphatase superfamily / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Metallo-dependent phosphatase-like / S1 domain profile. / Actins signature 1. / Actin, conserved site / Actins signature 2. / Actin/actin-like conserved site / Actins and actin-related proteins signature. / Ribosomal protein S1-like RNA-binding domain / S1 RNA binding domain / Actin / S1 domain / Actin family / Actin / ATPase, nucleotide binding domain / Nucleic acid-binding, OB-fold
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / : / Deoxyribonuclease-1 / Eukaryotic translation initiation factor 2 subunit 1 / Protein DP71L / Serine/threonine-protein phosphatase PP1-alpha catalytic subunit / Actin, alpha skeletal muscle
Similarity search - Component
Biological speciesAfrican swine fever virus
Homo sapiens (human)
Oryctolagus cuniculus (rabbit)
Bos taurus (domestic cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsReineke, L.C. / Dalwadi, U. / Croll, T. / Arthur, C. / Lee, D.J. / Frost, A. / Costa-Mattioli, M.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: bioRxiv / Year: 2025
Title: Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction.
Abstract: The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts ...The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts cognitive performance, primarily focusing on a PPP1R15B genetic variant associated with intellectual disability. By generating a novel mouse model that mimics this human condition, we revealed that this variant destabilizes the PPP1R15B•PP1 phosphatase complex, resulting in chronic ISR activation, impaired protein synthesis, and deficits in long-term memory. Importantly, we found that the cognitive and synaptic deficits in mice are directly due to ISR activation. Leveraging insights from evolutionary biology, we characterized DP71L, a viral orthologue of PPP1R15B, through detailed molecular and structural analyses, uncovering its mechanism of action as a potent pan-ISR inhibitor. Remarkably, we found that DP71L not only buffers cognitive decline associated with a wide array of conditions-including Down syndrome, Alzheimer's disease and aging-but also enhances long-term synaptic plasticity and memory in healthy mice. These findings highlight the promise of utilizing evolutionary insight to inform innovative therapeutic strategies.
History
DepositionFeb 13, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 9, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Protein DP71L
C: Serine/threonine-protein phosphatase PP1-alpha catalytic subunit
D: Actin, alpha skeletal muscle
E: Deoxyribonuclease-1
A: Eukaryotic translation initiation factor 2 subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,8418
Polymers141,2395
Non-polymers6023
Water00
1


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

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Components

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Protein , 5 types, 5 molecules BCDEA

#1: Protein Protein DP71L / MyD116 homolog


Mass: 8435.730 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) African swine fever virus / Gene: Pret-172 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P0C756
#2: Protein Serine/threonine-protein phosphatase PP1-alpha catalytic subunit / PP-1A


Mass: 37514.039 Da / Num. of mol.: 1 / Mutation: D64A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP1CA, PPP1A / Production host: Escherichia coli (E. coli)
References: UniProt: P62136, protein-serine/threonine phosphatase
#3: Protein Actin, alpha skeletal muscle / Alpha-actin-1


Mass: 42096.953 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P68135
#4: Protein Deoxyribonuclease-1 / Deoxyribonuclease I / DNase I


Mass: 31374.436 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (domestic cattle) / References: UniProt: P00639, deoxyribonuclease I
#5: Protein Eukaryotic translation initiation factor 2 subunit 1 / Eukaryotic translation initiation factor 2 subunit alpha / eIF-2-alpha / eIF-2A / eIF-2alpha / eIF2-alpha


Mass: 21817.863 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2S1, EIF2A / Production host: Escherichia coli (E. coli) / References: UniProt: P05198

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Non-polymers , 3 types, 3 molecules

#6: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mn
#7: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#8: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM

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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

ComponentName: PP1A holo-phosphatase complex with viral protein DP71L, G-actin, DNAseI, and substrate phospho-eIF2alpha (2-187)
Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.14 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHEPES1
2150 mMPotassium chlorideKCl1
31 mMManganese chlorideMnCl21
40.2 mMAdenosine triphosphateATP1
50.2 mMtris(2-carboxyethyl)phosphineTCEP1
61 mMCalcium chlorideCaCl21
SpecimenConc.: 5.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 278 K / Details: 3.5 uL volume, -5 blot force, 1.5 blot time

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5236
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.6.0particle selection
2EPU3.6.0image acquisition
4cryoSPARC4.6.0CTF correction
7UCSF ChimeraX1.7model fitting
8ISOLDE1.7model fitting
10ISOLDE1.7model refinement
11Servalcat0.4.99model refinement
12cryoSPARC4.6.0initial Euler assignment
13cryoSPARC4.6.0final Euler assignment
14cryoSPARC4.6.0classification
15cryoSPARC4.6.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1315944
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 309745 / Symmetry type: POINT
Atomic model buildingSource name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
ELECTRON MICROSCOPYs_bond_nonh_d0.0078002021296210.0118266292
ELECTRON MICROSCOPYs_angle_nonh_d1.66865284130301.82416117

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