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- PDB-6toq: Crystal structure of a PP2A B56y/HTLV-1 integrase complex -

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Basic information

Entry
Database: PDB / ID: 6toq
TitleCrystal structure of a PP2A B56y/HTLV-1 integrase complex
Components
  • Pol protein
  • Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform
KeywordsSIGNALING PROTEIN / Phosphatase / integrase / complex / SLiM / dephosphorylation / cell signalling / motif mimicry
Function / homology
Function and homology information


protein phosphatase type 2A complex / protein phosphatase regulator activity / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated ...protein phosphatase type 2A complex / protein phosphatase regulator activity / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated / CTNNB1 T41 mutants aren't phosphorylated / Disassembly of the destruction complex and recruitment of AXIN to the membrane / CTLA4 inhibitory signaling / Platelet sensitization by LDL / protein phosphatase activator activity / chromosome, centromeric region / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / Resolution of Sister Chromatid Cohesion / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / RHO GTPases Activate Formins / RAF activation / Degradation of beta-catenin by the destruction complex / DNA integration / Negative regulation of MAPK pathway / Separation of Sister Chromatids / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Regulation of TP53 Degradation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA recombination / nucleic acid binding / negative regulation of cell population proliferation / Golgi apparatus / signal transduction / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
Protein phosphatase 2A, regulatory B subunit, B56 / Protein phosphatase 2A regulatory B subunit (B56 family) / Integrase Zinc binding domain / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase DNA binding domain profile. / RNase H / Integrase core domain ...Protein phosphatase 2A, regulatory B subunit, B56 / Protein phosphatase 2A regulatory B subunit (B56 family) / Integrase Zinc binding domain / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase DNA binding domain profile. / RNase H / Integrase core domain / Integrase, catalytic core / Integrase catalytic domain profile. / Ribonuclease H domain / RNase H type-1 domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Armadillo-like helical / Armadillo-type fold / Ribonuclease H superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
Integrase / Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform
Similarity search - Component
Biological speciesHuman T-cell leukemia virus type I
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.164 Å
AuthorsMinnell, J.J. / Barski, M.S. / Maertens, G.N.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust107005 United Kingdom
CitationJournal: Nat Commun / Year: 2020
Title: Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ.
Authors: Michał S Barski / Jordan J Minnell / Zuzana Hodakova / Valerie E Pye / Andrea Nans / Peter Cherepanov / Goedele N Maertens /
Abstract: Human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus and the most oncogenic pathogen. Many of the ~20 million HTLV-1 infected people will develop severe leukaemia or an ALS-like motor ...Human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus and the most oncogenic pathogen. Many of the ~20 million HTLV-1 infected people will develop severe leukaemia or an ALS-like motor disease, unless a therapy becomes available. A key step in the establishment of infection is the integration of viral genetic material into the host genome, catalysed by the retroviral integrase (IN) enzyme. Here, we use X-ray crystallography and single-particle cryo-electron microscopy to determine the structure of the functional deltaretroviral IN assembled on viral DNA ends and bound to the B56γ subunit of its human host factor, protein phosphatase 2 A. The structure reveals a tetrameric IN assembly bound to two molecules of the phosphatase via a conserved short linear motif. Insight into the deltaretroviral intasome and its interaction with the host will be crucial for understanding the pattern of integration events in infected individuals and therefore bears important clinical implications.
History
DepositionDec 11, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 21, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
CCC: Pol protein
AAA: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform


Theoretical massNumber of molelcules
Total (without water)54,4732
Polymers54,4732
Non-polymers00
Water82946
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area870 Å2
ΔGint-7 kcal/mol
Surface area16220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.770, 58.770, 321.150
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Pol protein


Mass: 11171.691 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human T-cell leukemia virus type I / Gene: pol / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2 / Variant (production host): DE3 / References: UniProt: A0A1Y1CAL3
#2: Protein Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform / PP2A B subunit isoform B'-gamma / PP2A B subunit isoform B56-gamma / PP2A B subunit isoform PR61- ...PP2A B subunit isoform B'-gamma / PP2A B subunit isoform B56-gamma / PP2A B subunit isoform PR61-gamma / PP2A B subunit isoform R5-gamma / Renal carcinoma antigen NY-REN-29


Mass: 43301.129 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2R5C, KIAA0044 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2 / Variant (production host): DE3 / References: UniProt: Q13362
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 46 / Source method: isolated from a natural source / Formula: H2O

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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: 2.55 Å3/Da / Density % sol: 51.75 % / Description: Merged plates
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 0.1 M Na/KPO4 pH 6.2, 20-% 1,2-propanediol, 10% glycerol

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Data collection

DiffractionMean temperature: 277 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9192 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9192 Å / Relative weight: 1
ReflectionResolution: 3.16→80.29 Å / Num. obs: 10041 / % possible obs: 96.7 % / Redundancy: 1.4 % / CC1/2: 0.918 / Rmerge(I) obs: 0.167 / Rpim(I) all: 0.167 / Net I/σ(I): 3.3
Reflection shellResolution: 3.16→3.38 Å / Rmerge(I) obs: 0.489 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 1694 / CC1/2: 0.589 / % possible all: 94.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
Cootmodel building
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2JAK
Resolution: 3.164→80.29 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.873 / SU B: 27.25 / SU ML: 0.453 / Cross valid method: FREE R-VALUE / ESU R Free: 0.514
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2941 537 5.348 %
Rwork0.227 --
all0.231 --
obs-10041 95.912 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 57.582 Å2
Baniso -1Baniso -2Baniso -3
1-0.25 Å20 Å20 Å2
2--0.25 Å20 Å2
3----0.5 Å2
Refinement stepCycle: LAST / Resolution: 3.164→80.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2674 0 0 46 2720
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0122743
X-RAY DIFFRACTIONr_angle_refined_deg1.6551.633738
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.3545331
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.69822.969128
X-RAY DIFFRACTIONr_dihedral_angle_3_deg22.32215448
X-RAY DIFFRACTIONr_dihedral_angle_4_deg25.5981511
X-RAY DIFFRACTIONr_chiral_restr0.140.2364
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022060
X-RAY DIFFRACTIONr_nbd_refined0.2820.21466
X-RAY DIFFRACTIONr_nbtor_refined0.330.21879
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.160.295
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.3040.225
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1460.22
X-RAY DIFFRACTIONr_mcbond_it5.3165.9711339
X-RAY DIFFRACTIONr_mcangle_it8.1278.9221665
X-RAY DIFFRACTIONr_scbond_it6.4716.1241404
X-RAY DIFFRACTIONr_scangle_it9.8789.1082073
X-RAY DIFFRACTIONr_lrange_it13.17981.4754321
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.164-3.2470.382340.307646X-RAY DIFFRACTION89.5916
3.247-3.3350.331300.269640X-RAY DIFFRACTION93.8375
3.335-3.4320.343300.267673X-RAY DIFFRACTION97.2337
3.432-3.5380.352440.251614X-RAY DIFFRACTION97.4815
3.538-3.6540.351300.259649X-RAY DIFFRACTION98.8355
3.654-3.7820.319370.243587X-RAY DIFFRACTION96.5944
3.782-3.9250.37340.245587X-RAY DIFFRACTION97.1831
3.925-4.0850.282290.231547X-RAY DIFFRACTION98.4615
4.085-4.2670.254330.221540X-RAY DIFFRACTION95.5
4.267-4.4750.28330.199517X-RAY DIFFRACTION98.2143
4.475-4.7170.234320.178475X-RAY DIFFRACTION95.4802
4.717-5.0030.247260.168469X-RAY DIFFRACTION95.5598
5.003-5.3480.254300.197451X-RAY DIFFRACTION96.2
5.348-5.7770.327250.216416X-RAY DIFFRACTION98.4375
5.777-6.3280.353210.224382X-RAY DIFFRACTION96.1814
6.328-7.0740.312170.24363X-RAY DIFFRACTION96.4467
7.074-8.1680.428170.22313X-RAY DIFFRACTION93.2203
8.168-10.0020.265130.173274X-RAY DIFFRACTION93.1818
10.002-14.1380.183120.212229X-RAY DIFFRACTION96.4
14.138-80.290.264100.429132X-RAY DIFFRACTION89.8734

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