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- EMDB-9380: cryoEM structure of the truncated HIV-1 Vif/CBFbeta/A3F complex -

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Basic information

Entry
Database: EMDB / ID: EMD-9380
TitlecryoEM structure of the truncated HIV-1 Vif/CBFbeta/A3F complex
Map data
Sample
  • Complex: truncated Vif/CBFbeta/A3Fctd complex
    • Complex: 6xHis tagged hA3Fctd-40aa-hCBFbeta fusion
      • Protein or peptide: DNA dC->dU-editing enzyme APOBEC-3F
      • Protein or peptide: Core-binding factor subunit beta
    • Complex: alpha domain truncated HIV-1 Vif
      • Protein or peptide: Virion infectivity factor
  • Ligand: ZINC ION
KeywordsHuman antiviral restriction factor / HIV viral protein / ANTIVIRAL PROTEIN
Function / homology
Function and homology information


RUNX3 regulates RUNX1-mediated transcription / apolipoprotein B mRNA editing enzyme complex / RUNX1 regulates transcription of genes involved in BCR signaling / RUNX1 regulates transcription of genes involved in interleukin signaling / RUNX2 regulates bone development / core-binding factor complex / RUNX1 regulates expression of components of tight junctions / positive regulation of CD8-positive, alpha-beta T cell differentiation / RUNX2 regulates chondrocyte maturation / base conversion or substitution editing ...RUNX3 regulates RUNX1-mediated transcription / apolipoprotein B mRNA editing enzyme complex / RUNX1 regulates transcription of genes involved in BCR signaling / RUNX1 regulates transcription of genes involved in interleukin signaling / RUNX2 regulates bone development / core-binding factor complex / RUNX1 regulates expression of components of tight junctions / positive regulation of CD8-positive, alpha-beta T cell differentiation / RUNX2 regulates chondrocyte maturation / base conversion or substitution editing / single-stranded DNA cytosine deaminase / negative regulation of CD4-positive, alpha-beta T cell differentiation / DNA cytosine deamination / cytidine to uridine editing / deoxycytidine deaminase activity / cytidine deaminase activity / lymphocyte differentiation / clearance of foreign intracellular DNA / negative regulation of single stranded viral RNA replication via double stranded DNA intermediate / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / negative regulation of viral process / RUNX2 regulates genes involved in cell migration / virion component => GO:0044423 / RUNX2 regulates genes involved in differentiation of myeloid cells / Transcriptional regulation by RUNX2 / retrotransposon silencing / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / myeloid cell differentiation / RUNX3 Regulates Immune Response and Cell Migration / definitive hemopoiesis / DNA demethylation / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Regulation of RUNX1 Expression and Activity / negative regulation of viral genome replication / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / RUNX2 regulates osteoblast differentiation / RUNX3 regulates p14-ARF / viral life cycle / cell maturation / positive regulation of defense response to virus by host / virion component / P-body / Regulation of RUNX3 expression and activity / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / osteoblast differentiation / protein polyubiquitination / Transcriptional regulation of granulopoiesis / Regulation of RUNX2 expression and activity / RUNX1 regulates transcription of genes involved in differentiation of HSCs / defense response to virus / Estrogen-dependent gene expression / host cell cytoplasm / sequence-specific DNA binding / transcription by RNA polymerase II / transcription coactivator activity / ribonucleoprotein complex / innate immune response / regulation of transcription by RNA polymerase II / host cell plasma membrane / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / RNA binding / zinc ion binding / nucleoplasm / membrane / nucleus / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Retroviral Vif (Viral infectivity) protein / Retroviral Vif (Viral infectivity) protein / Core-binding factor, beta subunit / Core-binding factor, beta subunit superfamily / Core binding factor beta subunit / Novel AID APOBEC clade 2 / APOBEC/CMP deaminase, zinc-binding / Cytidine and deoxycytidylate deaminases zinc-binding region signature. / Cytidine and deoxycytidylate deaminase domain / Cytidine and deoxycytidylate deaminases domain profile. / Cytidine deaminase-like
Similarity search - Domain/homology
Virion infectivity factor / Virion infectivity factor / Core-binding factor subunit beta / DNA dC->dU-editing enzyme APOBEC-3F
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsHu Y / Xiong Y
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Center for Research Resources (NIH/NCRR)AI116313 United States
CitationJournal: Nat Struct Mol Biol / Year: 2019
Title: Structural basis of antagonism of human APOBEC3F by HIV-1 Vif.
Authors: Yingxia Hu / Belete A Desimmie / Henry C Nguyen / Samantha J Ziegler / Tat Cheung Cheng / John Chen / Jia Wang / Hongwei Wang / Kai Zhang / Vinay K Pathak / Yong Xiong /
Abstract: HIV-1 virion infectivity factor (Vif) promotes degradation of the antiviral APOBEC3 (A3) proteins through the host ubiquitin-proteasome pathway to enable viral immune evasion. Disrupting Vif-A3 ...HIV-1 virion infectivity factor (Vif) promotes degradation of the antiviral APOBEC3 (A3) proteins through the host ubiquitin-proteasome pathway to enable viral immune evasion. Disrupting Vif-A3 interactions to reinstate the A3-catalyzed suppression of human immunodeficiency virus type 1 (HIV-1) replication is a potential approach for antiviral therapeutics. However, the molecular mechanisms by which Vif recognizes A3 proteins remain elusive. Here we report a cryo-EM structure of the Vif-targeted C-terminal domain of human A3F in complex with HIV-1 Vif and the cellular cofactor core-binding factor beta (CBFβ) at 3.9-Å resolution. The structure shows that Vif and CBFβ form a platform to recruit A3F, revealing a direct A3F-recruiting role of CBFβ beyond Vif stabilization, and captures multiple independent A3F-Vif interfaces. Together with our biochemical and cellular studies, our structural findings establish the molecular determinants that are critical for Vif-mediated neutralization of A3F and provide a comprehensive framework of how HIV-1 Vif hijacks the host protein degradation machinery to counteract viral restriction by A3F.
History
DepositionDec 29, 2018-
Header (metadata) releaseDec 11, 2019-
Map releaseDec 11, 2019-
UpdateMar 20, 2024-
Current statusMar 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6nil
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_9380.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.05 Å
Density
Contour LevelBy AUTHOR: 0.025 / Movie #1: 0.025
Minimum - Maximum-0.05096353 - 0.110730626
Average (Standard dev.)0.00046493032 (±0.0038542699)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-58-58-58
Dimensions224224224
Spacing224224224
CellA=B=C: 235.19998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.051.051.05
M x/y/z224224224
origin x/y/z0.0000.0000.000
length x/y/z235.200235.200235.200
α/β/γ90.00090.00090.000
start NX/NY/NZ-51-35-11
NX/NY/NZ11110799
MAP C/R/S123
start NC/NR/NS-58-58-58
NC/NR/NS224224224
D min/max/mean-0.0510.1110.000

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Supplemental data

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Sample components

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Entire : truncated Vif/CBFbeta/A3Fctd complex

EntireName: truncated Vif/CBFbeta/A3Fctd complex
Components
  • Complex: truncated Vif/CBFbeta/A3Fctd complex
    • Complex: 6xHis tagged hA3Fctd-40aa-hCBFbeta fusion
      • Protein or peptide: DNA dC->dU-editing enzyme APOBEC-3F
      • Protein or peptide: Core-binding factor subunit beta
    • Complex: alpha domain truncated HIV-1 Vif
      • Protein or peptide: Virion infectivity factor
  • Ligand: ZINC ION

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Supramolecule #1: truncated Vif/CBFbeta/A3Fctd complex

SupramoleculeName: truncated Vif/CBFbeta/A3Fctd complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 17 KDa

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Supramolecule #2: 6xHis tagged hA3Fctd-40aa-hCBFbeta fusion

SupramoleculeName: 6xHis tagged hA3Fctd-40aa-hCBFbeta fusion / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Details: The N-terminus of human CBFbeta is fused to human A3Fctd through a 40 amino acid linker:GVDGSDEASELACPTPKEDGLAQQQTQLNLRSQATGSGSG
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: alpha domain truncated HIV-1 Vif

SupramoleculeName: alpha domain truncated HIV-1 Vif / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Human immunodeficiency virus 1

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Macromolecule #1: DNA dC->dU-editing enzyme APOBEC-3F

MacromoleculeName: DNA dC->dU-editing enzyme APOBEC-3F / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: single-stranded DNA cytosine deaminase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.433271 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSSHHHHHH SQDPNSMGKE ILRNPMEAMD PHIFYFHFKN LRKAYGRNES WLCFTMEVVK HHSPVSWKRG VFRNQVDPET GRHAERCFL SWFCDDILSP NTNYEVTWYT SWSPCPECAG EVAEFLARHS NVNLTIKTAR LYYFKDTDAA EGLRSLSQEG A SVEIMGYK ...String:
MGSSHHHHHH SQDPNSMGKE ILRNPMEAMD PHIFYFHFKN LRKAYGRNES WLCFTMEVVK HHSPVSWKRG VFRNQVDPET GRHAERCFL SWFCDDILSP NTNYEVTWYT SWSPCPECAG EVAEFLARHS NVNLTIKTAR LYYFKDTDAA EGLRSLSQEG A SVEIMGYK DFKYCWENFV YNDDEPFKPW DGLDYNFLDL DSKLQEILE

UniProtKB: DNA dC->dU-editing enzyme APOBEC-3F

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Macromolecule #2: Core-binding factor subunit beta

MacromoleculeName: Core-binding factor subunit beta / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.851043 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MPRVVPDQRS KFENEEFFRK LSRECEIKYT GFRDRPHEER QARFQNACRD GRSEIAFVAT GTNLSLQFFP ASWQGEQRQT PSREYVDLE REAGKVYLKA PMILNGVCVI WKGWIDLQRL DGMGCLEFDE ERAQQEDALA QQAFEEARRR TR

UniProtKB: Core-binding factor subunit beta

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Macromolecule #3: Virion infectivity factor

MacromoleculeName: Virion infectivity factor / type: protein_or_peptide / ID: 3
Details: Residues 114-157 was replaced with a 6 amino acid linker (EASEGS). The C-terminal residues 177-192 were deleted.
Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 16.736102 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MENRWQVMIV WQVDRMRINT WKRLVKHHMY ISRKAKDWFY RHHYESTNPK ISSEVHIPLG DAKLVITTYW GLHTGERDWH LGQGVSIEW RKKRYSTQVD PDLADQLIHL HYFDEASEGS QIKPPLPSVR KLTEDRWNK

UniProtKB: Virion infectivity factor, Virion infectivity factor

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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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

BufferpH: 8
GridDetails: unspecified
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: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 56.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionApplied symmetry - Point group: D2 (2x2 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 337256

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