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- EMDB-29488: Human APOBEC3H bound to HIV-1 Vif in complex with CBF-beta, ELOB,... -

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Entry
Database: EMDB / ID: EMD-29488
TitleHuman APOBEC3H bound to HIV-1 Vif in complex with CBF-beta, ELOB, ELOC, and CUL5
Map data
Sample
  • Complex: Hetero-hexameric complex of HIV-1 Vif and human APOBEC3H, CBF-beta, ELOB, ELOC, and CUL5
    • Protein or peptide: Core-binding factor subunit beta
    • Protein or peptide: Virion infectivity factor
    • Protein or peptide: DNA dC->dU-editing enzyme APOBEC-3H
    • RNA: RNA(5'-R(AP*UP*UP*UP*UP*UP*UP*UP*UP*U)-3')
    • RNA: RNA(5'-R(*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')
    • Protein or peptide: Cullin 5
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
  • Ligand: ZINC ION
  • Ligand: water
Keywordsvirus-host protein complex / ANTIVIRAL PROTEIN
Function / homology
Function and homology information


RUNX3 regulates RUNX1-mediated transcription / RUNX1 regulates transcription of genes involved in BCR signaling / mRNA Editing: C to U Conversion / Formation of the Editosome / 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 ...RUNX3 regulates RUNX1-mediated transcription / RUNX1 regulates transcription of genes involved in BCR signaling / mRNA Editing: C to U Conversion / Formation of the Editosome / 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 / single-stranded DNA cytosine deaminase / negative regulation of CD4-positive, alpha-beta T cell differentiation / DNA cytosine deamination / cytidine to uridine editing / negative regulation by host of viral genome replication / deoxycytidine deaminase activity / lymphocyte differentiation / cytidine deaminase activity / clearance of foreign intracellular DNA / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / negative regulation of single stranded viral RNA replication via double stranded DNA intermediate / RUNX2 regulates genes involved in cell migration / RUNX2 regulates genes involved in differentiation of myeloid cells / Transcriptional regulation by RUNX2 / cullin-RING ubiquitin ligase complex / retrotransposon silencing / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / myeloid cell differentiation / target-directed miRNA degradation / elongin complex / RUNX3 Regulates Immune Response and Cell Migration / VCB complex / definitive hemopoiesis / DNA demethylation / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Regulation of RUNX1 Expression and Activity / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / 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 / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / RUNX3 regulates p14-ARF / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / cell maturation / viral life cycle / RNA Polymerase II Pre-transcription Events / transcription corepressor binding / virion component / P-body / transcription elongation by RNA polymerase II / transcription initiation at RNA polymerase II promoter / TP53 Regulates Transcription of DNA Repair Genes / Vif-mediated degradation of APOBEC3G / Regulation of RUNX3 expression and activity / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / osteoblast differentiation / Regulation of expression of SLITs and ROBOs / protein polyubiquitination / Transcriptional regulation of granulopoiesis / Regulation of RUNX2 expression and activity / protein-macromolecule adaptor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Antigen processing: Ubiquitination & Proteasome degradation / Neddylation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / ubiquitin-dependent protein catabolic process / protein-containing complex assembly / defense response to virus / Estrogen-dependent gene expression / host cell cytoplasm / sequence-specific DNA binding / transcription by RNA polymerase II / transcription coactivator activity / protein ubiquitination / innate immune response / ubiquitin protein ligase binding / 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 / cytosol / cytoplasm
Similarity search - Function
APOBEC3H / APOBEC3 / 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 / APOBEC/CMP deaminase, zinc-binding / Cytidine and deoxycytidylate deaminases zinc-binding region signature. / Cytidine and deoxycytidylate deaminase domain ...APOBEC3H / APOBEC3 / 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 / APOBEC/CMP deaminase, zinc-binding / Cytidine and deoxycytidylate deaminases zinc-binding region signature. / Cytidine and deoxycytidylate deaminase domain / Cytidine and deoxycytidylate deaminases domain profile. / Cullin protein neddylation domain / Cullin, conserved site / Cullin family signature. / Elongin B / Cullin / Elongin-C / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin protein neddylation domain / Cytidine deaminase-like / Cullin / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin family / Cullin family profile. / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SKP1/BTB/POZ domain superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Cullin 5 / Virion infectivity factor / Core-binding factor subunit beta / Elongin-C / Elongin-B / DNA dC->dU-editing enzyme APOBEC-3H
Similarity search - Component
Biological speciesHomo sapiens (human) / Human immunodeficiency virus 1 / Escherichia coli (E. coli)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.24 Å
AuthorsIto F / Alvarez-Cabrera AL / Zhou ZH / Chen XS
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI150524 United States
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis of HIV-1 Vif-mediated E3 ligase targeting of host APOBEC3H.
Authors: Fumiaki Ito / Ana L Alvarez-Cabrera / Kyumin Kim / Z Hong Zhou / Xiaojiang S Chen /
Abstract: Human APOBEC3 (A3) cytidine deaminases are antiviral factors that are particularly potent against retroviruses. As a countermeasure, HIV-1 uses a viral infectivity factor (Vif) to target specific ...Human APOBEC3 (A3) cytidine deaminases are antiviral factors that are particularly potent against retroviruses. As a countermeasure, HIV-1 uses a viral infectivity factor (Vif) to target specific human A3s for proteasomal degradation. Vif recruits cellular transcription cofactor CBF-β and Cullin-5 (CUL5) RING E3 ubiquitin ligase to bind different A3s distinctively, but how this is accomplished remains unclear in the absence of the atomic structure of the complex. Here, we present the cryo-EM structures of HIV-1 Vif in complex with human A3H, CBF-β and components of CUL5 ubiquitin ligase (CUL5, ELOB, and ELOC). Vif nucleates the entire complex by directly binding four human proteins, A3H, CBF-β, CUL5, and ELOC. The structures reveal a large interface area between A3H and Vif, primarily mediated by an α-helical side of A3H and a five-stranded β-sheet of Vif. This A3H-Vif interface unveils the basis for sensitivity-modulating polymorphism of both proteins, including a previously reported gain-of-function mutation in Vif isolated from HIV/AIDS patients. Our structural and functional results provide insights into the remarkable interplay between HIV and humans and would inform development efforts for anti-HIV therapeutics.
History
DepositionJan 19, 2023-
Header (metadata) releaseSep 6, 2023-
Map releaseSep 6, 2023-
UpdateMay 1, 2024-
Current statusMay 1, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29488.png

Downloads & links

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Map

FileDownload / File: emd_29488.map.gz / Format: CCP4 / Size: 1.4 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.51 Å
Density
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.32533467 - 0.4400099
Average (Standard dev.)-0.00009275554 (±0.004770378)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions720720720
Spacing720720720
CellA=B=C: 367.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_29488_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_29488_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Hetero-hexameric complex of HIV-1 Vif and human APOBEC3H, CBF-bet...

EntireName: Hetero-hexameric complex of HIV-1 Vif and human APOBEC3H, CBF-beta, ELOB, ELOC, and CUL5
Components
  • Complex: Hetero-hexameric complex of HIV-1 Vif and human APOBEC3H, CBF-beta, ELOB, ELOC, and CUL5
    • Protein or peptide: Core-binding factor subunit beta
    • Protein or peptide: Virion infectivity factor
    • Protein or peptide: DNA dC->dU-editing enzyme APOBEC-3H
    • RNA: RNA(5'-R(AP*UP*UP*UP*UP*UP*UP*UP*UP*U)-3')
    • RNA: RNA(5'-R(*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')
    • Protein or peptide: Cullin 5
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
  • Ligand: ZINC ION
  • Ligand: water

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Supramolecule #1: Hetero-hexameric complex of HIV-1 Vif and human APOBEC3H, CBF-bet...

SupramoleculeName: Hetero-hexameric complex of HIV-1 Vif and human APOBEC3H, CBF-beta, ELOB, ELOC, and CUL5
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#8
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 120 KDa

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Macromolecule #1: Core-binding factor subunit beta

MacromoleculeName: Core-binding factor subunit beta / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.643814 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MPRVVPDQRS KFENEEFFRK LSRECEIKYT GFRDRPHEER QARFQNACRD GRSEIAFVAT GTNLSLQFFP ASWQGEQRQT PSREYVDLE REAGKVYLKA PMILNGVCVI WKGWIDLQRL DGMGCLEFDE ERAQQEDALA QQAFEEARRR TREFEDRD

UniProtKB: Core-binding factor subunit beta

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Macromolecule #2: Virion infectivity factor

MacromoleculeName: Virion infectivity factor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1 / Strain: pNL4-3
Molecular weightTheoretical: 21.160451 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GPMENRWQVM IVWQVDRMRI NTWKRLVKHH MYISRKAKDW FYRHHYESTH PKISSEVHIP LGDAKLVITT YWGLHTGERD WHLGQGVSI EWRKKRYSTQ VDPDLADQLI HLHYFDCFSE SAIRNTILGR IVSPRCEYQA GHNKVGSLQY LALAALIKPK Q IKPPLPSV RKLTEDRWNK

UniProtKB: Virion infectivity factor

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

MacromoleculeName: DNA dC->dU-editing enzyme APOBEC-3H / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: single-stranded DNA cytosine deaminase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.10341 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GPGGSGGMAL LTAETFRLQF NNKRRLRRPY YPRKALLCYQ LTPQNGSTPT RGYFENKKKC HAEICFINEI KSMGLDETQC YQVTCYLTW SPCSSCAWEL VDFIQAHDHL NLRIFASRLY YHWCKPQQDG LRLLCGSQVP VEVMGFPEFA DCWENFVDHE K PLSFNPYK MLEELDKNSR AIKRRLDRIK S

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

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Macromolecule #6: Cullin 5

MacromoleculeName: Cullin 5 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.61398 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GPAGSSLQFE DKWDFMRPIV LKLLRQESVT KQQWFDLFSD VHAVCLWDDK GPAKIHQALK EDILEFIKQA QARVLSHQDD TALLKAYIV EWRKFFTQCD ILPKPFCQLE ITLMGKQGSN KKSNVEDSIV RKLMLDTWNE SIFSNIKNRL QDSAMKLVHA E RLGEAFDS ...String:
GPAGSSLQFE DKWDFMRPIV LKLLRQESVT KQQWFDLFSD VHAVCLWDDK GPAKIHQALK EDILEFIKQA QARVLSHQDD TALLKAYIV EWRKFFTQCD ILPKPFCQLE ITLMGKQGSN KKSNVEDSIV RKLMLDTWNE SIFSNIKNRL QDSAMKLVHA E RLGEAFDS QLVIGVRESY VNLCSNPEDK LQIYRDNFEK AYLDSTERFY RTQAPSYLQQ NGVQNYMKYA DAKLKEEEKR AL RYLETRR ECNSVEALME CCVNALVTSF KETILAECQG MIKRNETEKL HLMFSLMDKV PNGIEPMLKD LEEHIIS

UniProtKB: Cullin 5

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Macromolecule #7: Elongin-B

MacromoleculeName: Elongin-B / type: protein_or_peptide / ID: 7 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.48803 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFLMIRRH KTTIFTDAKE SSTVFELKRI VEGILKRPPD EQRLYKDDQL LDDGKTLGEC GFTSQTARPQ APATVGLAFR ADDTFEALC IEPFSSPPEL PDV

UniProtKB: Elongin-B

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Macromolecule #8: Elongin-C

MacromoleculeName: Elongin-C / type: protein_or_peptide / ID: 8 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.84342 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MYVKLISSDG HEFIVKREHA LTSGTIKAML SGPGQFAENE TNEVNFREIP SHVLSKVCMY FTYKVRYTNS STEIPEFPIA PEIALELLM AANFLDC

UniProtKB: Elongin-C

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Macromolecule #4: RNA(5'-R(AP*UP*UP*UP*UP*UP*UP*UP*UP*U)-3')

MacromoleculeName: RNA(5'-R(AP*UP*UP*UP*UP*UP*UP*UP*UP*U)-3') / type: rna / ID: 4 / Number of copies: 1
Source (natural)Organism: Escherichia coli (E. coli)
Molecular weightTheoretical: 3.03974 KDa
SequenceString:
AUUUUUUUUU

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Macromolecule #5: RNA(5'-R(*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')

MacromoleculeName: RNA(5'-R(*AP*AP*AP*AP*AP*AP*AP*AP*A)-3') / type: rna / ID: 5 / Number of copies: 1
Source (natural)Organism: Escherichia coli (E. coli)
Molecular weightTheoretical: 2.917895 KDa
SequenceString:
AAAAAAAAA

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Macromolecule #9: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 9 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #10: water

MacromoleculeName: water / type: ligand / ID: 10 / Number of copies: 1 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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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

Concentration0.15 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 165000
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 14725 / Average exposure time: 3.5 sec. / 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: 3637921
Startup modelType of model: INSILICO MODEL
In silico model: Generated by stochastic gradient descent using ab intio reconstruction in cryoSPARC.
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 89986
FSC plot (resolution estimation)

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