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- PDB-7oug: STLV-1 intasome:B56 in complex with the strand-transfer inhibitor... -

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Basic information

Entry
Database: PDB / ID: 7oug
TitleSTLV-1 intasome:B56 in complex with the strand-transfer inhibitor raltegravir
Components
  • DNA (5'-D(*AP*CP*TP*GP*TP*GP*TP*TP*TP*GP*GP*CP*GP*CP*TP*TP*CP*TP*CP*TP*C)-3')
  • DNA (5'-D(*GP*AP*GP*AP*GP*AP*AP*GP*CP*GP*CP*CP*AP*AP*AP*CP*AP*CP*A)-3')
  • Integrase
  • Isoform 3 of PC4 and SFRS1-interacting protein,Isoform Gamma-2 of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform
KeywordsVIRAL PROTEIN / STLV-intasome / HTLV / integrase strand-transfer inhibitor / raltegravir.
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 / supercoiled DNA binding / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / Platelet sensitization by LDL / CTLA4 inhibitory signaling / 2-LTR circle formation / Formation of WDR5-containing histone-modifying complexes / Vpr-mediated nuclear import of PICs / protein phosphatase activator activity / Integration of provirus / APOBEC3G mediated resistance to HIV-1 infection / mRNA 5'-splice site recognition / chromosome, centromeric region / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / heterochromatin / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / Resolution of Sister Chromatid Cohesion / nuclear periphery / RHO GTPases Activate Formins / RAF activation / euchromatin / Degradation of beta-catenin by the destruction complex / DNA integration / RNA stem-loop binding / Negative regulation of MAPK pathway / Separation of Sister Chromatids / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Regulation of TP53 Degradation / response to heat / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / DNA-binding transcription factor binding / DNA recombination / proteasome-mediated ubiquitin-dependent protein catabolic process / response to oxidative stress / transcription coactivator activity / chromatin remodeling / negative regulation of cell population proliferation / chromatin binding / Golgi apparatus / signal transduction / positive regulation of transcription by RNA polymerase II / RNA binding / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
Protein phosphatase 2A, regulatory B subunit, B56 / Protein phosphatase 2A regulatory B subunit (B56 family) / Lens epithelium-derived growth factor, integrase-binding domain / HIV integrase-binding domain superfamily / Lens epithelium-derived growth factor (LEDGF) / TFIIS/LEDGF domain superfamily / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain ...Protein phosphatase 2A, regulatory B subunit, B56 / Protein phosphatase 2A regulatory B subunit (B56 family) / Lens epithelium-derived growth factor, integrase-binding domain / HIV integrase-binding domain superfamily / Lens epithelium-derived growth factor (LEDGF) / TFIIS/LEDGF domain superfamily / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain / Integrase Zinc binding domain / Integrase DNA binding domain / 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. / RNase H type-1 domain profile. / Ribonuclease H domain / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / 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
Chem-RLT / DNA / DNA (> 10) / PC4 and SFRS1-interacting protein / Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform / Pol protein
Similarity search - Component
Biological speciesSimian T-lymphotropic virus 1
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsBarski, M.S. / Ballandras-Colas, A. / Cronin, N.B. / Pye, V.E. / Cherepanov, P. / Maertens, G.N.
Funding support United Kingdom, United States, 4items
OrganizationGrant numberCountry
Wellcome Trust107005/Z/15Z United Kingdom
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)GM082251 United States
The Francis Crick InstituteFC001061 United Kingdom
Wellcome Trust206175/Z/17/Z United Kingdom
CitationJournal: Nat Commun / Year: 2021
Title: Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures.
Authors: Michal S Barski / Teresa Vanzo / Xue Zhi Zhao / Steven J Smith / Allison Ballandras-Colas / Nora B Cronin / Valerie E Pye / Stephen H Hughes / Terrence R Burke / Peter Cherepanov / Goedele N Maertens /
Abstract: Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this ...Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.
History
DepositionJun 11, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 18, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 6, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / em_admin / pdbx_database_proc / pdbx_seq_map_depositor_info
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update / _pdbx_seq_map_depositor_info.one_letter_code_mod
Revision 1.2Jul 17, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_initial_refinement_model
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update

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Structure visualization

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  • EMDB-13076
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Assembly

Deposited unit
D: Integrase
E: Integrase
F: Isoform 3 of PC4 and SFRS1-interacting protein,Isoform Gamma-2 of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform
I: DNA (5'-D(*AP*CP*TP*GP*TP*GP*TP*TP*TP*GP*GP*CP*GP*CP*TP*TP*CP*TP*CP*TP*C)-3')
J: DNA (5'-D(*GP*AP*GP*AP*GP*AP*AP*GP*CP*GP*CP*CP*AP*AP*AP*CP*AP*CP*A)-3')
A: Integrase
B: Integrase
C: Isoform 3 of PC4 and SFRS1-interacting protein,Isoform Gamma-2 of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform
K: DNA (5'-D(*AP*CP*TP*GP*TP*GP*TP*TP*TP*GP*GP*CP*GP*CP*TP*TP*CP*TP*CP*TP*C)-3')
L: DNA (5'-D(*GP*AP*GP*AP*GP*AP*AP*GP*CP*GP*CP*CP*AP*AP*AP*CP*AP*CP*A)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)333,44220
Polymers332,19410
Non-polymers1,24810
Water1448
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, homology
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area30120 Å2
ΔGint-201 kcal/mol
Surface area90120 Å2

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Components

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Protein , 2 types, 6 molecules DEABFC

#1: Protein
Integrase


Mass: 33943.539 Da / Num. of mol.: 4 / Mutation: A219E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Simian T-lymphotropic virus 1 / Gene: pol / Production host: Escherichia coli (E. coli) / Variant (production host): DE3 pLacI (Rosetta-2) / References: UniProt: Q4QY51
#2: Protein Isoform 3 of PC4 and SFRS1-interacting protein,Isoform Gamma-2 of 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: 80394.680 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: fusion construct containing human LEDGF (residues 1-324 thus without the IBD domain) (gene PSIP1; O75475)) and human B56gammma (residues 11-380) regulatory subunit of PP2A (gene PPP2R5C) (no ...Details: fusion construct containing human LEDGF (residues 1-324 thus without the IBD domain) (gene PSIP1; O75475)) and human B56gammma (residues 11-380) regulatory subunit of PP2A (gene PPP2R5C) (no space for these details below).,fusion construct containing human LEDGF (residues 1-324 thus without the IBD domain) (gene PSIP1; O75475)) and human B56gammma (residues 11-380) regulatory subunit of PP2A (gene PPP2R5C) (no space for these details below).
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2R5C, KIAA0044 / Production host: Escherichia coli (E. coli) / Variant (production host): LOBSTR(RIL) / References: UniProt: O75475, UniProt: Q13362

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DNA chain , 2 types, 4 molecules IKJL

#3: DNA chain DNA (5'-D(*AP*CP*TP*GP*TP*GP*TP*TP*TP*GP*GP*CP*GP*CP*TP*TP*CP*TP*CP*TP*C)-3')


Mass: 9221.909 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Simian T-lymphotropic virus 1
#4: DNA chain DNA (5'-D(*GP*AP*GP*AP*GP*AP*AP*GP*CP*GP*CP*CP*AP*AP*AP*CP*AP*CP*A)-3')


Mass: 8593.560 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Simian T-lymphotropic virus 1

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Non-polymers , 4 types, 18 molecules

#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#6: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-RLT / N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-di hydropyrimidine-4-carboxamide / RALTEGRAVIR, MK0518


Mass: 444.416 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H21FN6O5 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antiretroviral*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: Complex of STLV-1 MarB43 integrase with nascent viral DNA, the human PP2A B56 subunit and the inhibitor raltegravir
Type: COMPLEX
Details: Sample composition and source have been described in "macromolecules"
Entity ID: #1-#4 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.3311 MDa / Experimental value: NO
Buffer solutionpH: 6
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMBis tris propane1
20.3 MSodium chlorideNaCl1
SpecimenConc.: 0.76 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Complex was isolated by size exclusion chromatography
Specimen supportDetails: Glow-discharged for 4 min at 45 mA on an Emitech K100X instrument (Electron Microscopy Sciences) and covered with a layer of graphene oxide (Sigma-Aldrich, catalogue #763705) immediately before being used.
Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 295.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

SoftwareName: PHENIX / Version: dev_4155: / Classification: refinement
EM software
IDNameVersionCategory
1Gautomatch0.53particle selection
2EPUimage acquisition
4Gctf1.06CTF correction
7UCSF Chimera1.12model fitting
9Coot0.8.9.2model refinement
10PHENIXdev-4142model refinement
11cryoSPARCinitial Euler assignment
12RELION3.1final Euler assignment
13RELION3.1classification
14RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2840121
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 111051 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Details: 6Z2Y was fitted into the cryoEM map using Chimera. The model was adjusted to fit the map; metal ions and drug docked into the map manually using Coot. The final model was subjected to Phenix. ...Details: 6Z2Y was fitted into the cryoEM map using Chimera. The model was adjusted to fit the map; metal ions and drug docked into the map manually using Coot. The final model was subjected to Phenix.real_space_refine using C2 NCS, secondary structure and metal ion coordination restraints.
Atomic model buildingPDB-ID: 6Z2Y

6z2y
PDB Unreleased entry


Accession code: 6Z2Y
Details: 6Z2Y was fitted into the cryoEM map using Chimera. The model was adjusted to fit the map; metal ions and drug docked into the map manually using Coot. The final model was subjected to Phenix. ...Details: 6Z2Y was fitted into the cryoEM map using Chimera. The model was adjusted to fit the map; metal ions and drug docked into the map manually using Coot. The final model was subjected to Phenix.real_space_refine using C2 NCS, secondary structure and metal ion coordination restraints.
Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00315672
ELECTRON MICROSCOPYf_angle_d0.68821678
ELECTRON MICROSCOPYf_dihedral_angle_d18.3892582
ELECTRON MICROSCOPYf_chiral_restr0.0762408
ELECTRON MICROSCOPYf_plane_restr0.0042466

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