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- EMDB-43705: HIV-1 wild-type intasome core -

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Basic information

Entry
Database: EMDB / ID: EMD-43705
TitleHIV-1 wild-type intasome core
Map dataPrimary map
Sample
  • Complex: wild-type HIV-1 intasomes
    • Protein or peptide: Integrase
    • DNA: vDNA
    • DNA: vDNA
  • Ligand: MAGNESIUM ION
  • Ligand: ZINC ION
  • Ligand: (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
KeywordsHIV-1 / integrase / nucleoprotein complexes / INSTI / VIRAL PROTEIN
Function / homology
Function and homology information


DNA integration / viral genome integration into host DNA / establishment of integrated proviral latency / RNA-directed DNA polymerase activity / endonuclease activity / DNA recombination / symbiont entry into host cell / DNA binding / zinc ion binding
Similarity search - Function
Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase DNA binding domain profile. / Integrase core domain / Integrase, catalytic core ...Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase DNA binding domain profile. / Integrase core domain / Integrase, catalytic core / Integrase catalytic domain profile. / Ribonuclease H superfamily / Ribonuclease H-like superfamily
Similarity search - Domain/homology
Biological speciesHuman immunodeficiency virus 1
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLi M / Craigie R
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK) United States
CitationJournal: J Mol Biol / Year: 2024
Title: HIV-1 Integrase Assembles Multiple Species of Stable Synaptic Complex Intasomes That Are Active for Concerted DNA Integration In vitro.
Authors: Min Li / Renbin Yang / Xuemin Chen / Huaibin Wang / Rodolfo Ghirlando / Emilios K Dimitriadis / Robert Craigie /
Abstract: Retroviral DNA integration is mediated by nucleoprotein complexes (intasomes) in which a pair of viral DNA ends are bridged by a multimer of integrase (IN). Most of the high-resolution structures of ...Retroviral DNA integration is mediated by nucleoprotein complexes (intasomes) in which a pair of viral DNA ends are bridged by a multimer of integrase (IN). Most of the high-resolution structures of HIV-1 intasomes are based on an HIV-1 IN with an Sso7d protein domain fused to the N-terminus. Sso7d-IN aggregates much less than wild-type IN and has been critical for structural studies of HIV-1 intasomes. Unexpectedly, these structures revealed that the common core architecture that mediates catalysis could be assembled in various ways, giving rise to both tetrameric and dodecameric intasomes, together with other less well-characterized species. This differs from related retroviruses that assemble unique multimeric intasomes, although the number of protomers in the intasome varies between viruses. The question of whether the additional Sso7d domain contributes to the heterogeneity of HIV-1 intasomes is therefore raised. We have addressed this by biochemical and structural studies of intasomes assembled with wild-type HIV-1 IN. Negative stain and cryo-EM reveal a similar range of multimeric intasome species as with Sso7d-IN with the same common core architecture. Stacks of intasomes resulting from domain swapping are also seen with both wild-type and Sso7d-IN intasomes. The propensity to assemble multimeric intasome species is, therefore, an intrinsic property of HIV-1 IN and is not conferred by the presence of the Sso7d domain. The recently solved intasome structures of different retroviral species, which have been reported to be tetrameric, octameric, dodecameric, and hexadecameric, highlight how a common intasome core architecture can be assembled in different ways for catalysis.
History
DepositionFeb 13, 2024-
Header (metadata) releaseApr 17, 2024-
Map releaseApr 17, 2024-
UpdateApr 24, 2024-
Current statusApr 24, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43705.png

Downloads & links

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Map

FileDownload / File: emd_43705.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPrimary map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 360 pix.
= 378. Å		1.05 Å/pix.
x 360 pix.
= 378. Å		1.05 Å/pix.
x 360 pix.
= 378. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.05 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.016
Minimum - Maximum-0.021049248 - 0.06971362
Average (Standard dev.)0.000005866695 (±0.0016641753)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 377.99997 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_43705_additional_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half1 map

Fileemd_43705_half_map_1.map
AnnotationHalf1 map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half2 map

Fileemd_43705_half_map_2.map
AnnotationHalf2 map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : wild-type HIV-1 intasomes

EntireName: wild-type HIV-1 intasomes
Components
  • Complex: wild-type HIV-1 intasomes
    • Protein or peptide: Integrase
    • DNA: vDNA
    • DNA: vDNA
  • Ligand: MAGNESIUM ION
  • Ligand: ZINC ION
  • Ligand: (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide

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Supramolecule #1: wild-type HIV-1 intasomes

SupramoleculeName: wild-type HIV-1 intasomes / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: HIV-1 intasomes assembled with wild-type NL4-3 integrase
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 400 KDa

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Macromolecule #1: Integrase

MacromoleculeName: Integrase / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 32.658252 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GSHMFLDGID KAQEEHEKYH SNWRAMASDF NLPPVVAKEI VASCDKCQLK GEAMHGQVDC SPGIWQLDCT HLEGKVILVA VHVASGYIE AEVIPAETGQ ETAYFLLKLA GRWPVKTVHT DNGSNFTSTT VKAACWWAGI KQEFGIPYNP QSQGVIESMN K ELKKIIGQ ...String:
GSHMFLDGID KAQEEHEKYH SNWRAMASDF NLPPVVAKEI VASCDKCQLK GEAMHGQVDC SPGIWQLDCT HLEGKVILVA VHVASGYIE AEVIPAETGQ ETAYFLLKLA GRWPVKTVHT DNGSNFTSTT VKAACWWAGI KQEFGIPYNP QSQGVIESMN K ELKKIIGQ VRDQAEHLKT AVQMAVFIHN FKRKGGIGGY SAGERIVDII ATDIQTKELQ KQITKIQNFR VYYRDSRDPV WK GPAKLLW KGEGAVVIQD NSDIKVVPRR KAKIIRDYGK QMAGDDCVAS RQDED

UniProtKB: Integrase

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Macromolecule #2: vDNA

MacromoleculeName: vDNA / type: dna / ID: 2 / Number of copies: 2 / Classification: DNA
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 27.371412 KDa
SequenceString: (DA)(DC)(DT)(DG)(DC)(DT)(DA)(DG)(DA)(DG) (DA)(DT)(DT)(DT)(DT)(DC)(DC)(DA)(DC)(DA) (DC)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT) (DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT) (DT) (DT)(DT)(DT)(DT)(DT)(DT) ...String:
(DA)(DC)(DT)(DG)(DC)(DT)(DA)(DG)(DA)(DG) (DA)(DT)(DT)(DT)(DT)(DC)(DC)(DA)(DC)(DA) (DC)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT) (DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT) (DT) (DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT) (DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT) (DT)(DT) (DT)(DT)(DT)(DT)(DT)(DT)(DT) (DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT) (DT)(DT)(DT) (DT)(DT)(DT)(DT)(DT)(DT) (DT)(DT)(DT)(DT)

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Macromolecule #3: vDNA

MacromoleculeName: vDNA / type: dna / ID: 3 / Number of copies: 2 / Classification: DNA
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 8.374477 KDa
SequenceString:
(DA)(DA)(DA)(DA)(DA)(DA)(DA)(DA)(DG)(DT) (DG)(DT)(DG)(DG)(DA)(DA)(DA)(DA)(DT)(DC) (DT)(DC)(DT)(DA)(DG)(DC)(DA)

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #6: (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4...

MacromoleculeName: (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
type: ligand / ID: 6 / Number of copies: 2 / Formula: DLU
Molecular weightTheoretical: 419.379 Da
Chemical component information

ChemComp-DLU:
(4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide / medication, antiretroviral*YM / Dolutegravir

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.4 mg/mL
BufferpH: 6.2
GridModel: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.4000000000000001 µm / Nominal magnification: 105000
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 460363
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5u1c

Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 167000
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

5u1c


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8w09:
HIV-1 wild-type intasome core

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