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- EMDB-13076: STLV-1 intasome:B56 in complex with the strand-transfer inhibitor... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-13076 | |||||||||||||||
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Title | STLV-1 intasome:B56 in complex with the strand-transfer inhibitor raltegravir | |||||||||||||||
![]() | DeemEMenhancer highest target | |||||||||||||||
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![]() | STLV-intasome / HTLV / integrase strand-transfer inhibitor / raltegravir. / VIRAL PROTEIN | |||||||||||||||
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 | single particle reconstruction / cryo EM / Resolution: 3.1 Å | |||||||||||||||
![]() | Barski MS / Ballandras-Colas A | |||||||||||||||
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
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 92.4 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 26.8 KB 26.8 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 10.8 KB | Display | ![]() |
Images | ![]() | 127 KB | ||
Filedesc metadata | ![]() | 8.2 KB | ||
Others | ![]() ![]() ![]() | 7.2 MB 82.8 MB 82.9 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7ougMC ![]() 7oufC ![]() 7ouhC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | DeemEMenhancer highest target | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.1 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Additional map: denmod map which was used for model real space refinement
File | emd_13076_additional_1.map | ||||||||||||
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Annotation | denmod map which was used for model real space refinement | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half map 2
File | emd_13076_half_map_1.map | ||||||||||||
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Annotation | half map 2 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half map 1
File | emd_13076_half_map_2.map | ||||||||||||
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Annotation | half map 1 | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Complex of STLV-1 MarB43 integrase with nascent viral DNA, the hu...
Entire | Name: Complex of STLV-1 MarB43 integrase with nascent viral DNA, the human PP2A B56 subunit and the inhibitor raltegravir |
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Components |
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-Supramolecule #1: Complex of STLV-1 MarB43 integrase with nascent viral DNA, the hu...
Supramolecule | Name: Complex of STLV-1 MarB43 integrase with nascent viral DNA, the human PP2A B56 subunit and the inhibitor raltegravir type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 Details: Sample composition and source have been described in "macromolecules" |
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Molecular weight | Theoretical: 331.1 KDa |
-Macromolecule #1: Integrase
Macromolecule | Name: Integrase / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 33.943539 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: GPEFQLSPAK LHSFTHCGQA ALTLHGATTT EALNILHSCH ACRKNNPQHQ MPRGHIRRGL LPNHIWQGDI THFKYKNTLY RLHVWVDTF SGSVSATHKK RETSSEAISS LLHAIAHLGR PSHINTDNGP AYASQEFQHA CTSLAIRHTT HIPYNPTSSG L VERTNGIL ...String: GPEFQLSPAK LHSFTHCGQA ALTLHGATTT EALNILHSCH ACRKNNPQHQ MPRGHIRRGL LPNHIWQGDI THFKYKNTLY RLHVWVDTF SGSVSATHKK RETSSEAISS LLHAIAHLGR PSHINTDNGP AYASQEFQHA CTSLAIRHTT HIPYNPTSSG L VERTNGIL KTLLYKYFSD NPNLPMDNAL SVALWTINHL NVLTHCQKTR WQLHHSPRLP PIPEEKPVTT SKTHWYYFKI PG LNSRQWK GPQRALQEAA GAALIPVSDT AAQWIPWKLL KRAVCPRLAG DTADPKERDH QHHG UniProtKB: Pol protein |
-Macromolecule #2: Isoform 3 of PC4 and SFRS1-interacting protein,Isoform Gamma-2 of...
Macromolecule | Name: Isoform 3 of PC4 and SFRS1-interacting protein,Isoform Gamma-2 of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform type: protein_or_peptide / ID: 2 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). Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 80.39468 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: SMTRDFKPGD LIFAKMKGYP HWPARVDEVP DGAVKPPTNK LPIFFFGTHE TAFLGPKDIF PYSENKEKYG KPNKRKGFNE GLWEIDNNP KVKFSSQQAA TKQSNASSDV EVEEKETSVS KEDTDHEEKA SNEDVTKAVD ITTPKAARRG RKRKAEKQVE T EEAGVVTT ...String: SMTRDFKPGD LIFAKMKGYP HWPARVDEVP DGAVKPPTNK LPIFFFGTHE TAFLGPKDIF PYSENKEKYG KPNKRKGFNE GLWEIDNNP KVKFSSQQAA TKQSNASSDV EVEEKETSVS KEDTDHEEKA SNEDVTKAVD ITTPKAARRG RKRKAEKQVE T EEAGVVTT ATASVNLKVS PKRGRPAATE VKIPKPRGRP KMVKQPCPSE SDIITEEDKS KKKGQEEKQP KKQPKKDEEG QK EEDKPRK EPDKKEGKKE VESKRKNLAK TGVTSTSDSE EEGDDQEGEK KRKGGRNFQT AHRRNMLKGQ HEKEAADRKR KQE EQMETE FMVVDAANSN GPFQPVVLLH IRDVPPADQE KLFIQKLRQC CVLFDFVSDP LSDLKWKEVK RAALSEMVEY ITHN RNVIT EPIYPEVVHM FAVNMFRTLP PSSNPTGAEF DPEEDEPTLE AAWPHLQLVY EFFLRFLESP DFQPNIAKKY IDQKF VLQL LELFDSEDPR ERDFLKTTLH RIYGKFLGLR AYIRKQINNI FYRFIYETEH HNGIAELLEI LGSIINGFAL PLKEEH KIF LLKVLLPLHK VKSLSVYHPQ LAYCVVQFLE KDSTLTEPVV MALLKYWPKT HSPKEVMFLN ELEEILDVIE PSEFVKI ME PLFRQLAKCV SSPHFQVAER ALYYWNNEYI MSLISDNAAK ILPIMFPSLY RNSKT UniProtKB: PC4 and SFRS1-interacting protein, Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform |
-Macromolecule #3: DNA (5'-D(*AP*CP*TP*GP*TP*GP*TP*TP*TP*GP*GP*CP*GP*CP*TP*TP*CP*TP*...
Macromolecule | Name: 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') type: dna / ID: 3 / Number of copies: 2 / Classification: DNA |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 9.221909 KDa |
Sequence | String: (DA)(DC)(DT)(DG)(DT)(DG)(DT)(DT)(DT)(DG) (DG)(DC)(DG)(DC)(DT)(DT)(DC)(DT)(DC)(DT) (DC)(DC)(DC)(DG)(DG)(DA)(DG)(DA)(DG) (DA) |
-Macromolecule #4: DNA (5'-D(*GP*AP*GP*AP*GP*AP*AP*GP*CP*GP*CP*CP*AP*AP*AP*CP*AP*CP*...
Macromolecule | Name: DNA (5'-D(*GP*AP*GP*AP*GP*AP*AP*GP*CP*GP*CP*CP*AP*AP*AP*CP*AP*CP*A)-3') type: dna / ID: 4 / Number of copies: 2 / Classification: DNA |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 8.59356 KDa |
Sequence | String: (DT)(DC)(DT)(DC)(DT)(DC)(DC)(DG)(DG)(DG) (DA)(DG)(DA)(DG)(DA)(DA)(DG)(DC)(DG)(DC) (DC)(DA)(DA)(DA)(DC)(DA)(DC)(DA) |
-Macromolecule #5: ZINC ION
Macromolecule | Name: ZINC ION / type: ligand / ID: 5 / Number of copies: 4 / Formula: ZN |
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Molecular weight | Theoretical: 65.409 Da |
-Macromolecule #6: MAGNESIUM ION
Macromolecule | Name: MAGNESIUM ION / type: ligand / ID: 6 / Number of copies: 4 / Formula: MG |
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Molecular weight | Theoretical: 24.305 Da |
-Macromolecule #7: N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1...
Macromolecule | Name: 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 type: ligand / ID: 7 / Number of copies: 2 / Formula: RLT |
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Molecular weight | Theoretical: 444.416 Da |
-Macromolecule #8: water
Macromolecule | Name: water / type: ligand / ID: 8 / Number of copies: 8 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 0.76 mg/mL | |||||||||
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Buffer | pH: 6 Component:
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Grid | Model: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 240 sec. Details: 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. | |||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 295.15 K / Instrument: FEI VITROBOT MARK IV | |||||||||
Details | Complex was isolated by size exclusion chromatography |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Detector mode: COUNTING / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Initial model | PDB ID: ![]() 6z2y Chain - Source name: PDB / Chain - Initial model type: experimental model 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. |
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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. |
Refinement | Protocol: RIGID BODY FIT |
Output model | ![]() PDB-7oug: |