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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 | |||||||||||||||
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Title | Structure of the STLV intasome:B56 complex bound to the strand-transfer inhibitor XZ450 | |||||||||||||||
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![]() | VIRAL PROTEIN / STLV-1 intasome / integrase strand-transfer inhibitor / HTLV / raltegravir | |||||||||||||||
Function / homology | ![]() 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 / 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 / nuclear periphery / RHO GTPases Activate Formins / RAF activation / Degradation of beta-catenin by the destruction complex / euchromatin / 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 / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / response to heat / 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 | |||||||||||||||
Biological species | ![]() ![]() | |||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å | |||||||||||||||
![]() | Barski, M.S. / Ballandras-Colas, A. / Cronin, N.B. / Pye, V.E. / Cherepanov, P. / Maertens, G.N. | |||||||||||||||
Funding support | ![]() ![]()
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![]() | ![]() 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 |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 363.5 KB | Display | ![]() |
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PDB format | ![]() | 275.4 KB | Display | ![]() |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 13075MC ![]() 7ougC ![]() 7ouhC M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Protein , 2 types, 6 molecules DEABFC
#1: Protein | Mass: 33943.539 Da / Num. of mol.: 4 / Mutation: A219E Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #2: Protein | Mass: 80394.680 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-DNA chain , 2 types, 4 molecules IKJH
#3: DNA chain | Mass: 9221.909 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) ![]() #4: DNA chain | Mass: 8593.560 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) ![]() |
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-Non-polymers , 4 types, 22 molecules ![](data/chem/img/ZN.gif)
![](data/chem/img/MG.gif)
![](data/chem/img/1L0.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/MG.gif)
![](data/chem/img/1L0.gif)
![](data/chem/img/HOH.gif)
#5: Chemical | ChemComp-ZN / #6: Chemical | ChemComp-MG / #7: Chemical | #8: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: 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 | |||||||||||||||
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Molecular weight | Value: 0.3311 MDa / Experimental value: NO | |||||||||||||||
Buffer solution | pH: 6 | |||||||||||||||
Buffer component |
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Specimen | Conc.: 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 support | 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 ...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 | |||||||||||||||
Vitrification | Instrument: 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 |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Specimen holder | Cryogen: NITROGEN |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 9188 |
EM imaging optics | Energyfilter name: GIF Bioquantum |
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Processing
Software | Name: PHENIX / Version: dev_4155: / Classification: refinement | ||||||||||||||||||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 1539858 | ||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 78528 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT / Space: REAL | ||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 6Z2Y![]() 6z2y 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 | ||||||||||||||||||||||||||||||||||||||||||||
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