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

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Basic information

Entry
Database: PDB / ID: 8gcr
TitleHPV16 E6-E6AP-p53 complex
Components
  • Cellular tumor antigen p53
  • Maltose/maltodextrin-binding periplasmic protein,Protein E6
  • Ubiquitin-protein ligase E3A
KeywordsVIRAL PROTEIN / Complex / HPV / ubiquitin ligase / tumor suppressor
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 O157:H7 (bacteria)
Human papillomavirus type 16
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.38 Å
AuthorsBratkowski, M.A. / Wang, J.C.K. / Hao, Q. / Nile, A.H.
Funding support United States, 1items
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein,Protein E6
B: Cellular tumor antigen p53
R: Ubiquitin-protein ligase E3A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)190,3366
Polymers190,1403
Non-polymers1963
Water00
1


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

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Components

#1: Protein Maltose/maltodextrin-binding periplasmic protein,Protein E6 / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP


Mass: 61190.582 Da / Num. of mol.: 1 / Mutation: C87S,C104S,C118S,C147S
Source method: isolated from a genetically manipulated source
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.
Source: (gene. exp.) Escherichia coli O157:H7 (bacteria), (gene. exp.) Human papillomavirus type 16
Gene: malE, Z5632, ECs5017, E6 / Production host: Escherichia coli (E. coli) / References: UniProt: P0AEY0, UniProt: P03126
#2: Protein Cellular tumor antigen p53 / Antigen NY-CO-13 / Phosphoprotein p53 / Tumor suppressor p53


Mass: 24643.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TP53, P53 / Production host: Escherichia coli (E. coli) / References: UniProt: P04637
#3: Protein Ubiquitin-protein ligase E3A / E6AP ubiquitin-protein ligase / HECT-type ubiquitin transferase E3A / Human papillomavirus E6- ...E6AP ubiquitin-protein ligase / HECT-type ubiquitin transferase E3A / Human papillomavirus E6-associated protein / Oncogenic protein-associated protein E6-AP / Renal carcinoma antigen NY-REN-54


Mass: 104305.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBE3A, E6AP, EPVE6AP, HPVE6A / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q05086, HECT-type E3 ubiquitin transferase
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestN

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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-IDSource
1Ternary complex of HPV16 E6, E6AP, and p53COMPLEX#1-#30MULTIPLE SOURCES
2HPV16 E6 - MBP FusionCOMPLEX#11RECOMBINANT
3p53COMPLEX#21RECOMBINANT
4E6APCOMPLEX#31RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Escherichia coli (E. coli)83334
32Human papillomavirus type 16333760
43Homo sapiens (human)9606
54Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Escherichia coli (E. coli)562
33Escherichia coli (E. coli)562
44Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTrisC4H11NO31
2150 mMSodium ChlorideNaCl1
35 mMDTTC4H10O2S21
40.01 PercentCHAPSOC32H58N2O8S1
SpecimenConc.: 2.15 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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 FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 80.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
EM software
IDNameCategory
7UCSF Chimeramodel fitting
9REFMACmodel refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2349301
3D reconstructionResolution: 3.38 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 105794 / Symmetry type: POINT
Atomic model buildingAccession code: 4xr8 / Source name: PDB / Type: experimental model
RefinementCross valid method: NONE
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0047412
ELECTRON MICROSCOPYf_angle_d0.64910011
ELECTRON MICROSCOPYf_dihedral_angle_d4.895987
ELECTRON MICROSCOPYf_chiral_restr0.0421090
ELECTRON MICROSCOPYf_plane_restr0.0051302

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