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- PDB-7nxv: Crystal structure of the complex of DNase I/G-actin/PPP1R15A_582-621 -

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Basic information

Entry
Database: PDB / ID: 7nxv
TitleCrystal structure of the complex of DNase I/G-actin/PPP1R15A_582-621
Components
  • Actin, alpha skeletal muscle, intermediate form
  • Deoxyribonuclease-1
  • Protein phosphatase 1 regulatory subunit 15A
KeywordsHYDROLASE / hydrolase regulator / protein phosphatase 1 regulatory unit
Function / homology
Function and homology information


positive regulation of translational initiation in response to stress / positive regulation of endoplasmic reticulum stress-induced eIF2 alpha dephosphorylation / regulation of translational initiation by eIF2 alpha dephosphorylation / regulation of neutrophil mediated cytotoxicity / zymogen granule / regulation of acute inflammatory response / positive regulation of peptidyl-serine dephosphorylation / deoxyribonuclease I / protein phosphatase type 1 complex / negative regulation of protein dephosphorylation ...positive regulation of translational initiation in response to stress / positive regulation of endoplasmic reticulum stress-induced eIF2 alpha dephosphorylation / regulation of translational initiation by eIF2 alpha dephosphorylation / regulation of neutrophil mediated cytotoxicity / zymogen granule / regulation of acute inflammatory response / positive regulation of peptidyl-serine dephosphorylation / deoxyribonuclease I / protein phosphatase type 1 complex / negative regulation of protein dephosphorylation / Response of EIF2AK1 (HRI) to heme deficiency / neutrophil activation involved in immune response / protein localization to endoplasmic reticulum / deoxyribonuclease I activity / protein phosphatase regulator activity / protein phosphatase 1 binding / DNA catabolic process / cytoskeletal motor activator activity / negative regulation of phosphoprotein phosphatase activity / negative regulation of PERK-mediated unfolded protein response / tropomyosin binding / mesenchyme migration / troponin I binding / myosin heavy chain binding / protein phosphatase activator activity / filamentous actin / actin filament bundle / positive regulation of phosphoprotein phosphatase activity / skeletal muscle thin filament assembly / striated muscle thin filament / actin filament bundle assembly / skeletal muscle myofibril / actin monomer binding / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / skeletal muscle fiber development / stress fiber / titin binding / actin filament polymerization / response to endoplasmic reticulum stress / Downregulation of TGF-beta receptor signaling / filopodium / actin filament / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / calcium-dependent protein binding / lamellipodium / nuclear envelope / actin binding / cell body / mitochondrial outer membrane / hydrolase activity / regulation of cell cycle / protein domain specific binding / apoptotic process / DNA damage response / calcium ion binding / positive regulation of gene expression / endoplasmic reticulum membrane / protein kinase binding / Golgi apparatus / magnesium ion binding / endoplasmic reticulum / mitochondrion / DNA binding / extracellular region / ATP binding / membrane / identical protein binding / nucleus / cytosol / cytoplasm
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 / Endonuclease/exonuclease/phosphatase / Endonuclease/Exonuclease/phosphatase family ...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 / Endonuclease/exonuclease/phosphatase / Endonuclease/Exonuclease/phosphatase family / Endonuclease/exonuclease/phosphatase superfamily / Actins signature 1. / Actin, conserved site / Actins signature 2. / Actin/actin-like conserved site / Actins and actin-related proteins signature. / Actin / Actin family / Actin / ATPase, nucleotide binding domain
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / Protein phosphatase 1 regulatory subunit 15A / Deoxyribonuclease-1 / Actin, alpha skeletal muscle
Similarity search - Component
Biological speciesHomo sapiens (human)
Oryctolagus cuniculus (rabbit)
Bos taurus (cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsYan, Y. / Ron, D.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome TrustWT 2008/Z/16/Z United Kingdom
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: Higher-order phosphatase-substrate contacts terminate the integrated stress response.
Authors: Yahui Yan / Heather P Harding / David Ron /
Abstract: Many regulatory PPP1R subunits join few catalytic PP1c subunits to mediate phosphoserine and phosphothreonine dephosphorylation in metazoans. Regulatory subunits engage the surface of PP1c, locally ...Many regulatory PPP1R subunits join few catalytic PP1c subunits to mediate phosphoserine and phosphothreonine dephosphorylation in metazoans. Regulatory subunits engage the surface of PP1c, locally affecting flexible access of the phosphopeptide to the active site. However, catalytic efficiency of holophosphatases towards their phosphoprotein substrates remains unexplained. Here we present a cryo-EM structure of the tripartite PP1c-PPP1R15A-G-actin holophosphatase that terminates signaling in the mammalian integrated stress response (ISR) in the pre-dephosphorylation complex with its substrate, translation initiation factor 2α (eIF2α). G-actin, whose essential role in eIF2α dephosphorylation is supported crystallographically, biochemically and genetically, aligns the catalytic and regulatory subunits, creating a composite surface that engages the N-terminal domain of eIF2α to position the distant phosphoserine-51 at the active site. Substrate residues that mediate affinity for the holophosphatase also make critical contacts with eIF2α kinases. Thus, a convergent process of higher-order substrate recognition specifies functionally antagonistic phosphorylation and dephosphorylation in the ISR.
History
DepositionMar 19, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 29, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 20, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / diffrn_source / pdbx_initial_refinement_model
Item: _diffrn_source.pdbx_synchrotron_site

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Actin, alpha skeletal muscle, intermediate form
B: Deoxyribonuclease-1
C: Protein phosphatase 1 regulatory subunit 15A
D: Actin, alpha skeletal muscle, intermediate form
E: Protein phosphatase 1 regulatory subunit 15A
F: Deoxyribonuclease-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)153,53716
Polymers151,4336
Non-polymers2,10410
Water90150
1
A: Actin, alpha skeletal muscle, intermediate form
B: Deoxyribonuclease-1
C: Protein phosphatase 1 regulatory subunit 15A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,7688
Polymers75,7173
Non-polymers1,0525
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5640 Å2
ΔGint-57 kcal/mol
Surface area27590 Å2
MethodPISA
2
D: Actin, alpha skeletal muscle, intermediate form
E: Protein phosphatase 1 regulatory subunit 15A
F: Deoxyribonuclease-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,7688
Polymers75,7173
Non-polymers1,0525
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5540 Å2
ΔGint-59 kcal/mol
Surface area27360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.519, 107.807, 192.412
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 4 molecules ADBF

#1: Protein Actin, alpha skeletal muscle, intermediate form


Mass: 41862.613 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P68135
#2: Protein Deoxyribonuclease-1 / Deoxyribonuclease I / DNase I


Mass: 29092.574 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P00639, deoxyribonuclease I

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Protein/peptide / Sugars , 2 types, 4 molecules CE

#3: Protein/peptide Protein phosphatase 1 regulatory subunit 15A / Growth arrest and DNA damage-inducible protein GADD34 / Myeloid differentiation primary response ...Growth arrest and DNA damage-inducible protein GADD34 / Myeloid differentiation primary response protein MyD116 homolog


Mass: 4761.417 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP1R15A, GADD34 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O75807
#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE

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Non-polymers , 3 types, 58 molecules

#5: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#6: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.87 Å3/Da / Density % sol: 57.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 5 / Details: 10% PEG4000, 0.1M Acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9762 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Mar 31, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 2.55→55.12 Å / Num. obs: 59509 / % possible obs: 100 % / Redundancy: 13.2 % / CC1/2: 0.987 / Rmerge(I) obs: 0.315 / Net I/σ(I): 6.5
Reflection shellResolution: 2.55→2.62 Å / Redundancy: 13.8 % / Rmerge(I) obs: 1.701 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 4573 / CC1/2: 0.631 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2A42

2a42


Resolution: 2.55→55.11 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.902 / SU B: 11.864 / SU ML: 0.241 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.491 / ESU R Free: 0.279 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2478 2906 4.9 %RANDOM
Rwork0.2159 ---
obs0.2175 56449 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 93.08 Å2 / Biso mean: 36.137 Å2 / Biso min: 12.27 Å2
Baniso -1Baniso -2Baniso -3
1--0.89 Å20 Å2-0 Å2
2--1.46 Å20 Å2
3----0.57 Å2
Refinement stepCycle: final / Resolution: 2.55→55.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10476 0 124 50 10650
Biso mean--41.55 23.72 -
Num. residues----1341
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.01310832
X-RAY DIFFRACTIONr_bond_other_d0.0010.01710021
X-RAY DIFFRACTIONr_angle_refined_deg1.2091.65314734
X-RAY DIFFRACTIONr_angle_other_deg1.0831.58223074
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.53251335
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.95322550
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.729151771
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2871571
X-RAY DIFFRACTIONr_chiral_restr0.040.21469
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212236
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022470
LS refinement shellResolution: 2.55→2.616 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 223 -
Rwork0.305 4088 -
all-4311 -
obs--99.86 %

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