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- PDB-7ouf: Structure of the STLV intasome:B56 complex bound to the strand-tr... -

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Basic information

Entry
Database: PDB / ID: 7ouf
TitleStructure of the STLV intasome:B56 complex bound to the strand-transfer inhibitor XZ450
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-1 of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform
KeywordsVIRAL PROTEIN / STLV-1 intasome / integrase strand-transfer inhibitor / HTLV / 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 / CTLA4 inhibitory signaling / Platelet sensitization by LDL / 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 / RNA stem-loop binding / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / Resolution of Sister Chromatid Cohesion / nuclear periphery / RHO GTPases Activate Formins / RAF activation / euchromatin / 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 / response to heat / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA-binding transcription factor binding / DNA recombination / 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. / 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
Chem-1L0 / 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 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

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Structure visualization

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  • Deposited structure unit
  • Imaged by Jmol
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  • Superimposition on EM map
  • EMDB-13075
  • Imaged by UCSF Chimera
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Structure viewerMolecule:
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Assembly

Deposited unit
D: Integrase
E: Integrase
F: Isoform 3 of PC4 and SFRS1-interacting protein,Isoform Gamma-1 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-1 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')
H: 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)333,44420
Polymers332,19410
Non-polymers1,25010
Water21612
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, homology
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area29960 Å2
ΔGint-212 kcal/mol
Surface area90110 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-1 of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform / CLL-associated antigen KW-7 / Dense fine speckles 70 kDa protein / DFS 70 / Lens epithelium-derived ...CLL-associated antigen KW-7 / Dense fine speckles 70 kDa protein / DFS 70 / Lens epithelium-derived growth factor / Transcriptional coactivator p75/p52 / 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
Source: (gene. exp.) Homo sapiens (human) / Gene: PSIP1, DFS70, LEDGF, PSIP2, 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 IKJH

#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, 22 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-1L0 / 4-azanyl-~{N}-[[2,4-bis(fluoranyl)phenyl]methyl]-6-[3-(dimethylamino)-3-oxidanylidene-propyl]-1-oxidanyl-2-oxidanylidene-1,8-naphthyridine-3-carboxamide


Mass: 445.419 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H21F2N5O4 / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 12 / 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 drug inhibitor XZ450
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 chlorideNaClSodium chloride1
SpecimenConc.: 0.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Complex was isolated by size exclusion chromatography
Specimen supportDetails: UltraAuFoil R 1.2/1.3 Au 300-mesh grids (Electron Microscopy Sciences) were glow-discharged for 4 min at 45 mA on an Emitech K100X instrument (Electron Microscopy Sciences) and covered with ...Details: UltraAuFoil R 1.2/1.3 Au 300-mesh grids (Electron Microscopy Sciences) were 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 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 FIELDBright-field microscopy
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 9188
EM imaging opticsEnergyfilter name: GIF Bioquantum

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Processing

SoftwareName: PHENIX / Version: dev_4155: / Classification: refinement
EM software
IDNameVersionCategory
1Gautomatchv0.53particle selection
2EPUimage acquisition
4Gctfv1.06CTF correction
7UCSF Chimeramodel fitting
9cryoSPARCinitial Euler assignment
10RELION3.1final Euler assignment
11RELION3.1classification
12RELION3.13D reconstruction
13Cootmodel refinement
14PHENIXdev-4142model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1539858
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 78528 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 6Z2Y

6z2y
PDB Unreleased entry


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.
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00315672
ELECTRON MICROSCOPYf_angle_d0.5221676
ELECTRON MICROSCOPYf_dihedral_angle_d18.4672582
ELECTRON MICROSCOPYf_chiral_restr0.042406
ELECTRON MICROSCOPYf_plane_restr0.0052464

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