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- PDB-6nil: cryoEM structure of the truncated HIV-1 Vif/CBFbeta/A3F complex -

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Basic information

Entry
Database: PDB / ID: 6nil
TitlecryoEM structure of the truncated HIV-1 Vif/CBFbeta/A3F complex
Components
  • Core-binding factor subunit beta
  • DNA dC->dU-editing enzyme APOBEC-3F
  • Virion infectivity factor
KeywordsANTIVIRAL PROTEIN / Human antiviral restriction factor / HIV viral 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 / lymphocyte differentiation / cytidine deaminase activity / 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 / cell maturation / positive regulation of defense response to virus by host / viral life cycle / 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 / identical protein binding / nucleus / plasma membrane / cytoplasm
Similarity search - Function
APOBEC-like N-terminal domain / Polyomavirus Enhancer Binding Protein 2; Chain: A; / Core binding factor, beta subunit / 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 ...APOBEC-like N-terminal domain / Polyomavirus Enhancer Binding Protein 2; Chain: A; / Core binding factor, beta subunit / 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 / Beta Barrel / Mainly Beta
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 speciesHomo sapiens (human)
Human immunodeficiency virus 1
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsHu, Y. / Xiong, Y.
Funding support United States, 1items
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, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Author supporting evidence / Database references / Category: citation / citation_author / pdbx_audit_support
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _pdbx_audit_support.funding_organization
Revision 1.2Mar 20, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: DNA dC->dU-editing enzyme APOBEC-3F
B: Core-binding factor subunit beta
C: Virion infectivity factor
D: DNA dC->dU-editing enzyme APOBEC-3F
E: Core-binding factor subunit beta
F: Virion infectivity factor
G: DNA dC->dU-editing enzyme APOBEC-3F
H: Core-binding factor subunit beta
I: Virion infectivity factor
J: DNA dC->dU-editing enzyme APOBEC-3F
K: Core-binding factor subunit beta
L: Virion infectivity factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)236,34316
Polymers236,08212
Non-polymers2624
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
DNA dC->dU-editing enzyme APOBEC-3F / Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3F / A3F


Mass: 24433.271 Da / Num. of mol.: 4 / Fragment: C-terminal domain
Mutation: Y196D, H247G, C248R, F302K, W310K, Y314A, Q315A, K355D, K358D, F363D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APOBEC3F / Production host: Escherichia coli (E. coli)
References: UniProt: Q8IUX4, single-stranded DNA cytosine deaminase
#2: Protein
Core-binding factor subunit beta / CBF-beta / Polyomavirus enhancer-binding protein 2 beta subunit / PEBP2-beta / SL3-3 enhancer ...CBF-beta / Polyomavirus enhancer-binding protein 2 beta subunit / PEBP2-beta / SL3-3 enhancer factor 1 subunit beta / SL3/AKV core-binding factor beta subunit


Mass: 17851.043 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CBFB / Production host: Escherichia coli (E. coli) / References: UniProt: Q13951
#3: Protein
Virion infectivity factor / Vif / SOR protein


Mass: 16736.102 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: Residues 114-157 was replaced with a 6 amino acid linker (EASEGS). The C-terminal residues 177-192 were deleted.
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: vif / Production host: Escherichia coli (E. coli) / References: UniProt: P12504, UniProt: A0A346ARH7
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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

Component
IDNameTypeEntity IDParent-IDSourceDetails
1truncated Vif/CBFbeta/A3Fctd complexCOMPLEX#1-#30MULTIPLE SOURCES
26xHis tagged hA3Fctd-40aa-hCBFbeta fusionCOMPLEX#1-#21RECOMBINANTThe N-terminus of human CBFbeta is fused to human A3Fctd through a 40 amino acid linker:GVDGSDEASELACPTPKEDGLAQQQTQLNLRSQATGSGSG
3alpha domain truncated HIV-1 VifCOMPLEX#31RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.25 MDaNO
210.046 MDaNO
310.017 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Human immunodeficiency virus 111676
32Homo sapiens (human)9606
43Human immunodeficiency virus 111676
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Escherichia coli (E. coli)562
32Escherichia coli (E. coli)562
43Escherichia coli (E. coli)562
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Image recordingElectron dose: 56 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0257 / Classification: refinement
CTF correctionType: NONE
SymmetryPoint symmetry: D2 (2x2 fold dihedral)
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 337256 / Symmetry type: POINT

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