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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


sperm entry / positive regulation of Golgi lumen acidification / symbiont-mediated suppression of host transcription / regulation of ubiquitin-dependent protein catabolic process / symbiont-mediated suppression of host apoptosis / prostate gland growth / HECT-type E3 ubiquitin transferase / negative regulation of helicase activity / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression ...sperm entry / positive regulation of Golgi lumen acidification / symbiont-mediated suppression of host transcription / regulation of ubiquitin-dependent protein catabolic process / symbiont-mediated suppression of host apoptosis / prostate gland growth / HECT-type E3 ubiquitin transferase / negative regulation of helicase activity / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / Activation of NOXA and translocation to mitochondria / regulation of cell cycle G2/M phase transition / oligodendrocyte apoptotic process / negative regulation of miRNA processing / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / regulation of Cdc42 protein signal transduction / mRNA transcription / bone marrow development / positive regulation of programmed necrotic cell death / circadian behavior / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / RUNX3 regulates CDKN1A transcription / glucose catabolic process to lactate via pyruvate / 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 / regulation of DNA damage response, signal transduction by p53 class mediator / histone deacetylase regulator activity / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / negative regulation of neuroblast proliferation / mitochondrial DNA repair / T cell lineage commitment / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / thymocyte apoptotic process / B cell lineage commitment / TP53 Regulates Transcription of Caspase Activators and Caspases / entrainment of circadian clock by photoperiod / cardiac septum morphogenesis / androgen receptor signaling pathway / negative regulation of mitophagy / negative regulation of DNA replication / Zygotic genome activation (ZGA) / positive regulation of release of cytochrome c from mitochondria / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / negative regulation of telomere maintenance via telomerase / necroptotic process / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / SUMOylation of transcription factors / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / intrinsic apoptotic signaling pathway by p53 class mediator / rRNA transcription / negative regulation of reactive oxygen species metabolic process / Transcriptional Regulation by VENTX / regulation of proteolysis / cellular response to UV-C / replicative senescence / general transcription initiation factor binding / cellular response to actinomycin D / progesterone receptor signaling pathway / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / positive regulation of RNA polymerase II transcription preinitiation complex assembly / carbohydrate transmembrane transporter activity / neuroblast proliferation / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / maltose binding / positive regulation of execution phase of apoptosis / Pyroptosis / viral process / hematopoietic stem cell differentiation / maltose transport / response to X-ray / maltodextrin transmembrane transport / embryonic organ development / chromosome organization / type II interferon-mediated signaling pathway / postsynaptic cytosol / somitogenesis / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / hematopoietic progenitor cell differentiation / glial cell proliferation / negative regulation of fibroblast proliferation / positive regulation of cardiac muscle cell apoptotic process
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

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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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