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- PDB-9s29: MVV CSC intasome in complex with LEDGF -

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Basic information

Entry
Database: PDB / ID: 9s29
TitleMVV CSC intasome in complex with LEDGF
Components
  • EV272
  • EV306
  • Gag-Pol polyprotein
  • PC4 and SFRS1-interacting protein
KeywordsVIRAL PROTEIN / integrase / LEDGF / p75 / MVV / DNA
Function / homology
Function and homology information


dUTP diphosphatase / dUTP diphosphatase activity / nucleotide metabolic process / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / ribonuclease H / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / supercoiled DNA binding / 2-LTR circle formation / Vpr-mediated nuclear import of PICs ...dUTP diphosphatase / dUTP diphosphatase activity / nucleotide metabolic process / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / ribonuclease H / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / supercoiled DNA binding / 2-LTR circle formation / Vpr-mediated nuclear import of PICs / Formation of WDR5-containing histone-modifying complexes / mRNA 5'-splice site recognition / Integration of provirus / APOBEC3G mediated resistance to HIV-1 infection / heterochromatin / nuclear periphery / exoribonuclease H / exoribonuclease H activity / DNA integration / euchromatin / viral genome integration into host DNA / establishment of integrated proviral latency / RNA-directed DNA polymerase / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / viral capsid / response to heat / DNA recombination / response to oxidative stress / DNA-directed DNA polymerase / DNA-binding transcription factor binding / aspartic-type endopeptidase activity / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase activity / transcription coactivator activity / chromatin remodeling / viral translational frameshifting / chromatin binding / symbiont entry into host cell / positive regulation of transcription by RNA polymerase II / proteolysis / DNA binding / RNA binding / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
Lens epithelium-derived growth factor, integrase-binding domain / HIV integrase-binding domain superfamily / Lens epithelium-derived growth factor (LEDGF) / dUTPase-like / dUTPase / dUTPase, trimeric / dUTPase-like superfamily / TFIIS/LEDGF domain superfamily / gag protein p24 N-terminal domain / domain with conserved PWWP motif ...Lens epithelium-derived growth factor, integrase-binding domain / HIV integrase-binding domain superfamily / Lens epithelium-derived growth factor (LEDGF) / dUTPase-like / dUTPase / dUTPase, trimeric / dUTPase-like superfamily / TFIIS/LEDGF domain superfamily / gag protein p24 N-terminal domain / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain / Reverse transcriptase connection / Reverse transcriptase connection domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase-like, N-terminal / 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 / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Reverse transcriptase (RNA-dependent DNA polymerase) / Retrovirus capsid, C-terminal / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Ribonuclease H superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
DNA / DNA (> 10) / PC4 and SFRS1-interacting protein / Gag-Pol polyprotein
Similarity search - Component
Biological speciesMaedi visna virus
Homo sapiens (human)
DNA molecule (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsPunch, E.K. / Hope, J. / Cherepanov, P.
Funding support United States, United Kingdom, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U54AI170791 United States
Wellcome TrustCC2058 United Kingdom
Medical Research Council (MRC, United Kingdom)CC2058 United Kingdom
Cancer Research UKCC2058 United Kingdom
CitationJournal: Nat Commun / Year: 2026
Title: Core nucleosomes are refractory to lentiviral DNA integration.
Authors: Joshua Hope / Emma Punch / Nicola J Cook / Matthew R Singer / Dhira Joshi / Parmit K Singh / Andrea Nans / Nathan P Sweeney / Willem Vanderlinden / Alan N Engelman / Peter Cherepanov /
Abstract: HIV-1 and other lentiviruses hijack the cellular chromatin-binding protein LEDGF/p75 to facilitate integration into active transcription units. However, the mechanism of chromatin engagement by ...HIV-1 and other lentiviruses hijack the cellular chromatin-binding protein LEDGF/p75 to facilitate integration into active transcription units. However, the mechanism of chromatin engagement by lentiviral intasomes and the structural role of LEDGF/p75 in this process remain poorly understood. To address these gaps, we studied the activities of native HIV-1 preintegration complexes and in vitro-assembled lentiviral intasomes in the presence of chromatinized target DNA. While LEDGF/p75 was both essential and minimally sufficient to enhance lentiviral integration into chromatin containing histone H3 trimethylated on Lys36, it unexpectedly facilitated integration outside of the nucleosome core particles. LEDGF/p75 additionally inhibited integration into unmodified chromatin in a dose-dependent manner, promoting integration into naked DNA. To explore the structural foundation for these activities, we imaged maedi-visna virus intasomes saturated with LEDGF/p75 before and after strand transfer by cryogenic electron microscopy. The structures revealed that the host factor alters the target DNA binding platform of the lentiviral intasome, imposing significant constraints on the path and configuration of target DNA to impede nucleosome engagement. Our results establish the preference of lentiviral intasomes for linker DNA regions within H3K36Me3-enriched chromatin and show that LEDGF/p75 plays a specific structural role at the viral-host target DNA interface.
History
DepositionJul 21, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 29, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Gag-Pol polyprotein
B: Gag-Pol polyprotein
C: Gag-Pol polyprotein
D: Gag-Pol polyprotein
E: Gag-Pol polyprotein
F: Gag-Pol polyprotein
G: Gag-Pol polyprotein
H: Gag-Pol polyprotein
W: EV306
X: EV272
a: PC4 and SFRS1-interacting protein
b: PC4 and SFRS1-interacting protein
c: PC4 and SFRS1-interacting protein
d: PC4 and SFRS1-interacting protein
e: PC4 and SFRS1-interacting protein
f: PC4 and SFRS1-interacting protein
I: Gag-Pol polyprotein
J: Gag-Pol polyprotein
K: Gag-Pol polyprotein
L: Gag-Pol polyprotein
M: Gag-Pol polyprotein
N: Gag-Pol polyprotein
O: Gag-Pol polyprotein
P: Gag-Pol polyprotein
Y: EV306
Z: EV272
g: PC4 and SFRS1-interacting protein
h: PC4 and SFRS1-interacting protein
i: PC4 and SFRS1-interacting protein
j: PC4 and SFRS1-interacting protein
k: PC4 and SFRS1-interacting protein
l: PC4 and SFRS1-interacting protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,266,18548
Polymers1,265,13832
Non-polymers1,04716
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Gag-Pol polyprotein


Mass: 32368.826 Da / Num. of mol.: 16
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Maedi visna virus (strain KV1772) / Strain: KV1772 / Gene: pol / Production host: Escherichia coli (E. coli) / References: UniProt: P35956
#2: DNA chain EV306


Mass: 6456.146 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) DNA molecule (others)
#3: DNA chain EV272


Mass: 5815.762 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) DNA molecule (others)
#4: Protein
PC4 and SFRS1-interacting protein / 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


Mass: 60224.453 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PSIP1, DFS70, LEDGF, PSIP2 / Production host: Escherichia coli (E. coli) / References: UniProt: O75475
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestN
Has protein modificationN

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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: MVV CSC intasome in complex with LEDGF / Type: COMPLEX
Details: Integrase and LEDGF were produced in E. coli. The complex was assembled in vitro.
Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 0.902 MDa / Experimental value: NO
Source (natural)Organism: Visna-maedi virus / Strain: KV1772
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 6.5
SpecimenEmbedding applied: YES / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: 150 mM NaCl, 20 mM BisTris pH 6.5, 3mM CaCl2
Specimen supportDetails: Graphene oxide was functionalised with amine-PEG4-DBCO
Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
EM embeddingMaterial: vitreous ice
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 3300 nm / Nominal defocus min: 1500 nm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 40.8 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)
EM imaging opticsEnergyfilter name: TFS Selectris / Energyfilter slit width: 7 eV

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
7UCSF Chimeramodel fitting
9RELION4.0.0initial Euler assignment
10cryoSPARC4.5.3final Euler assignment
11cryoSPARC4.5.3classification
12cryoSPARC4.5.33D reconstruction
13PHENIX1.21.2_5419model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 167347 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
17U32

7u32

17U321PDBexperimental model
23HPH

3hph

13HPH2PDBexperimental model
RefinementHighest resolution: 2.8 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00244474
ELECTRON MICROSCOPYf_angle_d0.40560368
ELECTRON MICROSCOPYf_dihedral_angle_d12.21216930
ELECTRON MICROSCOPYf_chiral_restr0.0396606
ELECTRON MICROSCOPYf_plane_restr0.0037462

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