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- EMDB-29941: HPV16 E6-E6AP-p53 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-29941
TitleHPV16 E6-E6AP-p53 complex
Map data
Sample
  • Complex: Ternary complex of HPV16 E6, E6AP, and p53
    • Complex: HPV16 E6 - MBP Fusion
      • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Protein E6
    • Complex: p53
      • Protein or peptide: Cellular tumor antigen p53
    • Complex: E6AP
      • Protein or peptide: Ubiquitin-protein ligase E3A
  • Ligand: ZINC ION
KeywordsComplex / HPV / ubiquitin ligase / tumor suppressor / VIRAL PROTEIN
Function / homology
Function and homology information


: / symbiont-mediated suppression of host transcription / regulation of ubiquitin-dependent protein catabolic process / symbiont-mediated suppression of host apoptosis / HECT-type E3 ubiquitin transferase / transcription regulator activator activity / negative regulation of helicase activity / signal transduction by p53 class mediator / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression ...: / symbiont-mediated suppression of host transcription / regulation of ubiquitin-dependent protein catabolic process / symbiont-mediated suppression of host apoptosis / HECT-type E3 ubiquitin transferase / transcription regulator activator activity / negative regulation of helicase activity / signal transduction by p53 class mediator / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / regulation of cell cycle G2/M phase transition / negative regulation of G1 to G0 transition / Transcriptional activation of cell cycle inhibitor p21 / negative regulation of pentose-phosphate shunt / Activation of NOXA and translocation to mitochondria / ATP-dependent DNA/DNA annealing activity / oligodendrocyte apoptotic process / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / bone marrow development / cellular response to actinomycin D / circadian behavior / regulation of Cdc42 protein signal transduction / positive regulation of programmed necrotic cell death / RUNX3 regulates CDKN1A transcription / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / mRNA transcription / Regulation of TP53 Activity through Association with Co-factors / Urea cycle / ER overload response / hematopoietic stem cell differentiation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / TP53 Regulates Transcription of Caspase Activators and Caspases / intrinsic apoptotic signaling pathway by p53 class mediator / entrainment of circadian clock by photoperiod / Zygotic genome activation (ZGA) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / PI5P Regulates TP53 Acetylation / positive regulation of release of cytochrome c from mitochondria / Association of TriC/CCT with target proteins during biosynthesis / hematopoietic progenitor cell differentiation / negative regulation of telomere maintenance via telomerase / progesterone receptor signaling pathway / SUMOylation of transcription factors / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / response to progesterone / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / replicative senescence / Transcriptional Regulation by VENTX / TFIID-class transcription factor complex binding / viral process / regulation of proteolysis / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / Pyroptosis / determination of adult lifespan / positive regulation of RNA polymerase II transcription preinitiation complex assembly / general transcription initiation factor binding / negative regulation of fibroblast proliferation / positive regulation of execution phase of apoptosis / carbohydrate transmembrane transporter activity / type II interferon-mediated signaling pathway / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / maltose binding / maltose transport / maltodextrin transmembrane transport / postsynaptic cytosol / cellular response to glucose starvation / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / core promoter sequence-specific DNA binding / cis-regulatory region sequence-specific DNA binding / protein autoubiquitination / Regulation of TP53 Activity through Acetylation / intrinsic apoptotic signaling pathway / mitotic G1 DNA damage checkpoint signaling / proteasome complex / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of TORC1 signaling / 14-3-3 protein binding / response to gamma radiation / protein K48-linked ubiquitination / MDM2/MDM4 family protein binding / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / protein phosphatase 2A binding / DNA damage response, signal transduction by p53 class mediator / positive regulation of protein ubiquitination / transcription initiation-coupled chromatin remodeling / molecular function activator activity / Regulation of PTEN gene transcription / tumor necrosis factor-mediated signaling pathway / cellular response to ionizing radiation / cellular response to xenobiotic stimulus / TP53 Regulates Metabolic Genes / brain development / PDZ domain binding / TP53 Regulates Transcription of DNA Repair Genes / cellular response to gamma radiation / mRNA 3'-UTR binding / Regulation of NF-kappa B signaling
Similarity search - Function
Ubiquitin-protein ligase E3A / Ubiquitin-protein ligase E3A, N-terminal zinc-binding domain / Ubiquitin-protein ligase E3A, N-terminal zinc-binding domain superfamily / Amino-terminal Zinc-binding domain of ubiquitin ligase E3A / Ubiquitin-protein ligase E3B/C / E6 early regulatory protein / E6 superfamily / Early Protein (E6) / HECT domain / HECT, E3 ligase catalytic domain ...Ubiquitin-protein ligase E3A / Ubiquitin-protein ligase E3A, N-terminal zinc-binding domain / Ubiquitin-protein ligase E3A, N-terminal zinc-binding domain superfamily / Amino-terminal Zinc-binding domain of ubiquitin ligase E3A / Ubiquitin-protein ligase E3B/C / E6 early regulatory protein / E6 superfamily / Early Protein (E6) / HECT domain / HECT, E3 ligase catalytic domain / HECT-domain (ubiquitin-transferase) / HECT domain profile. / Domain Homologous to E6-AP Carboxyl Terminus with / Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / : / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / p53-like transcription factor, DNA-binding / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein
Similarity search - Domain/homology
Protein E6 / Cellular tumor antigen p53 / Maltose/maltodextrin-binding periplasmic protein / Ubiquitin-protein ligase E3A
Similarity search - Component
Biological speciesEscherichia coli (E. coli) / Homo sapiens (human) / Human papillomavirus type 16
Methodsingle particle reconstruction / cryo EM / Resolution: 3.38 Å
AuthorsBratkowski MA / Wang JCK / Hao Q / Nile AH
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Nat Commun / Year: 2024
Title: Structure of the p53 degradation complex from HPV16.
Authors: John C K Wang / Hannah T Baddock / Amirhossein Mafi / Ian T Foe / Matthew Bratkowski / Ting-Yu Lin / Zena D Jensvold / Magdalena Preciado López / David Stokoe / Dan Eaton / Qi Hao / Aaron H Nile /
Abstract: Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3- ...Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3-ligase E6AP, also known as UBE3A, to promote degradation of the tumor suppressor, p53. In this study, we present a single-particle cryoEM structure of the full-length E6AP protein in complex with HPV16 E6 (16E6) and p53, determined at a resolution of ~3.3 Å. Our structure reveals extensive protein-protein interactions between 16E6 and E6AP, explaining their picomolar binding affinity. These findings shed light on the molecular basis of the ternary complex, which has been pursued as a potential therapeutic target for HPV-driven cervical, anal, and oropharyngeal cancers over the last two decades. Understanding the structural and mechanistic underpinnings of this complex is crucial for developing effective therapies to combat HPV-induced cancers. Our findings may help to explain why previous attempts to disrupt this complex have failed to generate therapeutic modalities and suggest that current strategies should be reevaluated.
History
DepositionMar 2, 2023-
Header (metadata) releaseMar 6, 2024-
Map releaseMar 6, 2024-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29941.png

Downloads & links

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Map

FileDownload / File: emd_29941.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 400 pix.
= 332. Å		0.83 Å/pix.
x 400 pix.
= 332. Å		0.83 Å/pix.
x 400 pix.
= 332. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.457
Minimum - Maximum-2.7096984 - 4.5795302
Average (Standard dev.)-0.00056465843 (±0.055722095)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 332.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_29941_msk_1.map
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Half map: #2

Fileemd_29941_half_map_1.map
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Half map: #1

Fileemd_29941_half_map_2.map
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Sample components

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Entire : Ternary complex of HPV16 E6, E6AP, and p53

EntireName: Ternary complex of HPV16 E6, E6AP, and p53
Components
  • Complex: Ternary complex of HPV16 E6, E6AP, and p53
    • Complex: HPV16 E6 - MBP Fusion
      • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Protein E6
    • Complex: p53
      • Protein or peptide: Cellular tumor antigen p53
    • Complex: E6AP
      • Protein or peptide: Ubiquitin-protein ligase E3A
  • Ligand: ZINC ION

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Supramolecule #1: Ternary complex of HPV16 E6, E6AP, and p53

SupramoleculeName: Ternary complex of HPV16 E6, E6AP, and p53 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Supramolecule #2: HPV16 E6 - MBP Fusion

SupramoleculeName: HPV16 E6 - MBP Fusion / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Escherichia coli (E. coli)

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Supramolecule #3: p53

SupramoleculeName: p53 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: E6AP

SupramoleculeName: E6AP / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Maltose/maltodextrin-binding periplasmic protein,Protein E6

MacromoleculeName: Maltose/maltodextrin-binding periplasmic protein,Protein E6
type: protein_or_peptide / ID: 1
Details: The cysteine to serine mutations are in the protein E6 portion of the chimeric construct.,The cysteine to serine mutations are in the protein E6 portion of the chimeric construct.
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human papillomavirus type 16
Molecular weightTheoretical: 61.190582 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY ...String:
MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY AFKYENGKYD IKDVGVDNAG AKAGLTFLVD LIKNKHMNAD TDYSIAEAAF NKGETAMTIN GPWAWSNIDT SK VNYGVTV LPTFKGQPSK PFVGVLSAGI NAASPNKELA KEFLENYLLT DEGLEAVNKD KPLGAVALKS YEEELAKDPR IAA TMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGRQ TVDEALKDAQ TRITKGGGGS ENLYFQGMHQ KRTAMFQDPQ ERPR KLPQL CTELQTTIHD IILECVYCKQ QLLRREVYDF AFRDLCIVYR DGNPYAVCDK CLKFYSKISE YRHYSYSLYG TTLEQ QYNK PLSDLLIRCI NCQKPLSPEE KQRHLDKKQR FHNIRGRWTG RCMSCSRSSR TRRETQL

UniProtKB: Maltose/maltodextrin-binding periplasmic protein, Protein E6

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Macromolecule #2: Cellular tumor antigen p53

MacromoleculeName: Cellular tumor antigen p53 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.64393 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GSSSVPSQKT YQGSYGFRLG FLHSGTAKSV TCTYSPALNK MFCQLAKTCP VQLWVDSTPP PGTRVRAMAI YKQSQHMTEV VRRCPHHER CSDSDGLAPP QHLIRVEGNL RVEYLDDRNT FRHSVVVPYE PPEVGSDCTT IHYNYMCNSS CMGGMNRRPI L TIITLEDS ...String:
GSSSVPSQKT YQGSYGFRLG FLHSGTAKSV TCTYSPALNK MFCQLAKTCP VQLWVDSTPP PGTRVRAMAI YKQSQHMTEV VRRCPHHER CSDSDGLAPP QHLIRVEGNL RVEYLDDRNT FRHSVVVPYE PPEVGSDCTT IHYNYMCNSS CMGGMNRRPI L TIITLEDS SGNLLGRNSF EVRVCACPGR DRRTEEENLR KKGEPHHELP PGSTKRALPN NT

UniProtKB: Cellular tumor antigen p53

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Macromolecule #3: Ubiquitin-protein ligase E3A

MacromoleculeName: Ubiquitin-protein ligase E3A / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: HECT-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 104.305281 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MEKLHQCYWK SGEPQSDDIE ASRMKRAAAK HLIERYYHQL TEGCGNEACT NEFCASCPTF LRMDNNAAAI KALELYKINA KLCDPHPSK KGASSAYLEN SKGAPNNSCS EIKMNKKGAR IDFKDVTYLT EEKVYEILEL CREREDYSPL IRVIGRVFSS A EALVQSFR ...String:
MEKLHQCYWK SGEPQSDDIE ASRMKRAAAK HLIERYYHQL TEGCGNEACT NEFCASCPTF LRMDNNAAAI KALELYKINA KLCDPHPSK KGASSAYLEN SKGAPNNSCS EIKMNKKGAR IDFKDVTYLT EEKVYEILEL CREREDYSPL IRVIGRVFSS A EALVQSFR KVKQHTKEEL KSLQAKDEDK DEDEKEKAAC SAAAMEEDSE ASSSRIGDSS QGDNNLQKLG PDDVSVDIDA IR RVYTRLL SNEKIETAFL NALVYLSPNV ECDLTYHNVY SRDPNYLNLF IIVMENRNLH SPEYLEMALP LFCKAMSKLP LAA QGKLIR LWSKYNADQI RRMMETFQQL ITYKVISNEF NSRNLVNDDD AIVAASKCLK MVYYANVVGG EVDTNHNEED DEEP IPESS ELTLQELLGE ERRNKKGPRV DPLETELGVK TLDCRKPLIP FEEFINEPLN EVLEMDKDYT FFKVETENKF SFMTC PFIL NAVTKNLGLY YDNRIRMYSE RRITVLYSLV QGQQLNPYLR LKVRRDHIID DALVRLEMIA MENPADLKKQ LYVEFE GEQ GVDEGGVSKE FFQLVVEEIF NPDIGMFTYD ESTKLFWFNP SSFETEGQFT LIGIVLGLAI YNNCILDVHF PMVVYRK LM GKKGTFRDLG DSHPVLYQSL KDLLEYEGNV EDDMMITFQI SQTDLFGNPM MYDLKENGDK IPITNENRKE FVNLYSDY I LNKSVEKQFK AFRRGFHMVT NESPLKYLFR PEEIELLICG SRNLDFQALE ETTEYDGGYT RDSVLIREFW EIVHSFTDE QKRLFLQFTT GTDRAPVGGL GKLKMIIAKN GPDTERLPTS HTCFNVLLLP EYSSKEKLKE RLLKAITYAK GFGMLENLYF QGHHHHHHG LNDIFEAQKI EWHE

UniProtKB: Ubiquitin-protein ligase E3A

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 3 / 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

Concentration2.15 mg/mL
BufferpH: 7
Component:
ConcentrationFormulaName
50.0 mMC4H11NO3Tris
150.0 mMNaClSodium Chloride
5.0 mMC4H10O2S2DTT
0.01 PercentC32H58N2O8SCHAPSO
GridModel: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 30 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 80.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2349301
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4xr8

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.38 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 105794
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

4xr8


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-8gcr:
HPV16 E6-E6AP-p53 complex

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