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- EMDB-45601: Human E3 ligase E6AP in complex with HPV16-E6 and p53 -

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Basic information

Entry
Database: EMDB / ID: EMD-45601
TitleHuman E3 ligase E6AP in complex with HPV16-E6 and p53
Map data
Sample
  • Complex: Ternary complex of E6AP with viral factor E6 and neosubstrate p53
    • Protein or peptide: Ubiquitin-protein ligase E3A
    • Protein or peptide: Immunoglobulin G-binding protein G/Cellular tumor antigen p53 fusion protein
    • Protein or peptide: Protein E6
KeywordsComplex / Viral / Ubiquitination / LIGASE
Function / homology
Function and homology information


sperm entry / positive regulation of Golgi lumen acidification / symbiont-mediated suppression of host transcription / negative regulation of dendritic spine morphogenesis / motor learning / regulation of ubiquitin-dependent protein catabolic process / symbiont-mediated perturbation of host apoptosis / prostate gland growth / HECT-type E3 ubiquitin transferase / activation of GTPase activity ...sperm entry / positive regulation of Golgi lumen acidification / symbiont-mediated suppression of host transcription / negative regulation of dendritic spine morphogenesis / motor learning / regulation of ubiquitin-dependent protein catabolic process / symbiont-mediated perturbation of host apoptosis / prostate gland growth / HECT-type E3 ubiquitin transferase / activation of GTPase activity / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / negative regulation of helicase activity / 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 / regulation of fibroblast apoptotic process / intrinsic apoptotic signaling pathway in response to hypoxia / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / glucose catabolic process to lactate via pyruvate / positive regulation of mitochondrial membrane permeability / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / RUNX3 regulates CDKN1A transcription / IgG binding / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / 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 / T cell lineage commitment / mitochondrial DNA repair / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / B cell lineage commitment / thymocyte apoptotic process / TP53 Regulates Transcription of Caspase Activators and Caspases / negative regulation of mitophagy / cardiac septum morphogenesis / negative regulation of DNA replication / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / negative regulation of telomere maintenance via telomerase / Zygotic genome activation (ZGA) / positive regulation of release of cytochrome c from mitochondria / Association of TriC/CCT with target proteins during biosynthesis / necroptotic process / locomotory exploration behavior / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / rRNA transcription / 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 / androgen receptor signaling pathway / T cell proliferation involved in immune response / negative regulation of reactive oxygen species metabolic process / positive regulation of execution phase of apoptosis / Transcriptional Regulation by VENTX / regulation of proteolysis / postsynaptic cytosol / replicative senescence / cellular response to UV-C / general transcription initiation factor binding / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to actinomycin D / neuroblast proliferation / positive regulation of RNA polymerase II transcription preinitiation complex assembly / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / response to X-ray / type II interferon-mediated signaling pathway / hematopoietic stem cell differentiation / Pyroptosis / chromosome organization / viral process / embryonic organ development / somitogenesis / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / glial cell proliferation / hematopoietic progenitor cell differentiation / protein K48-linked ubiquitination / progesterone receptor signaling pathway / core promoter sequence-specific DNA binding
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) / IgG-binding B / B 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) / IgG-binding B / B domain / M protein-type anchor domain / GA-like domain / GA-like domain / HECT domain / HECT, E3 ligase catalytic domain / HECT-domain (ubiquitin-transferase) / HECT domain profile. / Domain Homologous to E6-AP Carboxyl Terminus with / Immunoglobulin/albumin-binding domain superfamily / 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 / YSIRK Gram-positive signal peptide / LPXTG cell wall anchor motif / Gram-positive cocci surface proteins LPxTG motif profile. / LPXTG cell wall anchor domain / p53-like transcription factor, DNA-binding
Similarity search - Domain/homology
Protein E6 / Cellular tumor antigen p53 / Immunoglobulin G-binding protein G / Ubiquitin-protein ligase E3A
Similarity search - Component
Biological speciesHomo sapiens (human) / Human papillomavirus 16
Methodsingle particle reconstruction / cryo EM / Resolution: 3.54 Å
AuthorsKenny S / Das C
Funding support United States, 3 items
OrganizationGrant numberCountry
Other privateP30CA023168
American Heart Association905924/SK/2021 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32 GM132024 United States
CitationJournal: Structure / Year: 2025
Title: Structure of E6AP in complex with HPV16-E6 and p53 reveals a novel ordered domain important for E3 ligase activation.
Authors: Sebastian Kenny / Shalini Iyer / Clinton A Gabel / Natalia Tegenfeldt / Andrew G DeMarco / Mark C Hall / Leifu Chang / V Jo Davisson / Scott Vande Pol / Chittaranjan Das /
Abstract: High-risk human papillomavirus E6 oncoprotein is a model system for the recognition and degradation of cellular p53 tumor suppressor protein. There remains a gap in the understanding of the ubiquitin ...High-risk human papillomavirus E6 oncoprotein is a model system for the recognition and degradation of cellular p53 tumor suppressor protein. There remains a gap in the understanding of the ubiquitin transfer reaction, including placement of the E6AP catalytic HECT domain of the ligase concerning the p53 substrate and how E6 itself is protected from ubiquitination. We determined the cryoelectron microscopy (cryo-EM) structure of the E6AP/E6/p53 complex, related the structure to in vivo modeling of the tri-molecular complex, and identified structural interactions associated with activation of the ubiquitin ligase function. The structure reveals that the N-terminal ordered domain (NOD) in E6AP has a terminal alpha helix that mediates the interaction of the NOD with the HECT domain of E6AP and protects the HPV-E6 protein from ubiquitination. In addition, this NOD helix is required for E6AP ligase function by contributing to the affinity of the E6-E6AP association, modulating E6 substrate recognition, while displacing UbcH7.
History
DepositionJul 2, 2024-
Header (metadata) releaseJan 8, 2025-
Map releaseJan 8, 2025-
UpdateMar 19, 2025-
Current statusMar 19, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45601.png

Downloads & links

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Map

FileDownload / File: emd_45601.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.316
Minimum - Maximum-3.2597888 - 5.208333
Average (Standard dev.)0.0016058313 (±0.088757455)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 220.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_45601_half_map_1.map
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Half map: #1

Fileemd_45601_half_map_2.map
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Sample components

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Entire : Ternary complex of E6AP with viral factor E6 and neosubstrate p53

EntireName: Ternary complex of E6AP with viral factor E6 and neosubstrate p53
Components
  • Complex: Ternary complex of E6AP with viral factor E6 and neosubstrate p53
    • Protein or peptide: Ubiquitin-protein ligase E3A
    • Protein or peptide: Immunoglobulin G-binding protein G/Cellular tumor antigen p53 fusion protein
    • Protein or peptide: Protein E6

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Supramolecule #1: Ternary complex of E6AP with viral factor E6 and neosubstrate p53

SupramoleculeName: Ternary complex of E6AP with viral factor E6 and neosubstrate p53
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Ubiquitin-protein ligase E3A

MacromoleculeName: Ubiquitin-protein ligase E3A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: HECT-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 102.982867 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGSSHHHHHH SSGLVPRGSH MEKLHQCYWK SGEPQSDDIE ASRMKRAAAK HLIERYYHQL TEGCGNEACT NEFCASCPTF LRMDNNAAA IKALELYKIN AKLCDPHPSK KGASSAYLEN SKGAPNNSCS EIKMNKKGAR IDFKDVTYLT EEKVYEILEL C REREDYSP ...String:
MGSSHHHHHH SSGLVPRGSH MEKLHQCYWK SGEPQSDDIE ASRMKRAAAK HLIERYYHQL TEGCGNEACT NEFCASCPTF LRMDNNAAA IKALELYKIN AKLCDPHPSK KGASSAYLEN SKGAPNNSCS EIKMNKKGAR IDFKDVTYLT EEKVYEILEL C REREDYSP LIRVIGRVFS SAEALVQSFR KVKQHTKEEL KSLQAKDEDK DEDEKEKAAC SAAAMEEDSE ASSSRIGDSS QG DNNLQKL GPDDVSVDID AIRRVYTRLL SNEKIETAFL NALVYLSPNV ECDLTYHNVY SRDPNYLNLF IIVMENRNLH SPE YLEMAL PLFCKAMSKL PLAAQGKLIR LWSKYNADQI RRMMETFQQL ITYKVISNEF NSRNLVNDDD AIVAASKCLK MVYY ANVVG GEVDTNHNEE DDEEPIPESS ELTLQELLGE ERRNKKGPRV DPLETELGVK TLDCRKPLIP FEEFINEPLN EVLEM DKDY TFFKVETENK FSFMTCPFIL NAVTKNLGLY YDNRIRMYSE RRITVLYSLV QGQQLNPYLR LKVRRDHIID DALVRL EMI AMENPADLKK QLYVEFEGEQ GVDEGGVSKE FFQLVVEEIF NPDIGMFTYD ESTKLFWFNP SSFETEGQFT LIGIVLG LA IYNNCILDVH FPMVVYRKLM GKKGTFRDLG DSHPVLYQSL KDLLEYEGNV EDDMMITFQI SQTDLFGNPM MYDLKENG D KIPITNENRK EFVNLYSDYI LNKSVEKQFK AFRRGFHMVT NESPLKYLFR PEEIELLICG SRNLDFQALE ETTEYDGGY TRDSVLIREF WEIVHSFTDE QKRLFLQFTT GTDRAPVGGL GKLKMIIAKN GPDTERLPTS HTCFNVLLLP EYSSKEKLKE RLLKAITYA KGFGML

UniProtKB: Ubiquitin-protein ligase E3A

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Macromolecule #2: Immunoglobulin G-binding protein G/Cellular tumor antigen p53 fus...

MacromoleculeName: Immunoglobulin G-binding protein G/Cellular tumor antigen p53 fusion protein
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.801734 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGHHHHHHSS GMTYKLILNG KTLKGETTTE AVDAATAEKV FKQYANDNGV DGEWTYDDAT KTFTVTEEFS SGSSGENLYF QGSHMEEPQ SDPSVEPPLS QETFSDLWKL LPENNVLSPL PSQAMDDLML SPDDIEQWFT EDPGPDEAPR MPEAAPPVAP A PAAPTPAA ...String:
MGHHHHHHSS GMTYKLILNG KTLKGETTTE AVDAATAEKV FKQYANDNGV DGEWTYDDAT KTFTVTEEFS SGSSGENLYF QGSHMEEPQ SDPSVEPPLS QETFSDLWKL LPENNVLSPL PSQAMDDLML SPDDIEQWFT EDPGPDEAPR MPEAAPPVAP A PAAPTPAA PAPAPSWPLS SSVPSQKTYQ GSYGFRLGFL HSGTAKSVTC TYSPALNKLF CQLAKTCPVQ LWVDSTPPPG TR VRAMAIY KQSQHMTEVV RRCPHHERCS DSDGLAPPQH LIRVEGNLRA EYLDDRNTFR HSVVVPYEPP EVGSDCTTIH YNY MCYSSC MGGMNRRPIL TIITLEDSSG NLLGRDSFEV RVCACPGRDR RTEEENLRKK GEPHHELPPG STKRALPNNT

UniProtKB: Immunoglobulin G-binding protein G, Cellular tumor antigen p53

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Macromolecule #3: Protein E6

MacromoleculeName: Protein E6 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human papillomavirus 16
Molecular weightTheoretical: 18.365369 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MFQDPQERPR KLPQLCTELQ TTIHDIILEC VYCKQQLLRR EVYDFAFRDL CIVYRDGNPY AVCDKCLKFY SKISEYRHYC YSLYGTTLE QQYNKPLCDL LIRCINCQKP LCPEEKQRHL DKKQRFHNIR GRWTGRCMSC CRSSRTRRET QL

UniProtKB: Protein E6

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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

Concentration0.25 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 279 K
Detailsmonodisperse, further purified by SEC

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 5548 / Average exposure time: 3.192 sec. / Average electron dose: 1.52 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1591147
Startup modelType of model: INSILICO MODEL / In silico model: AlphaFold2 model for E6AP and p53
Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 3.54 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2.0) / Number images used: 238679
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.0)
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC (ver. 3.2.0)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: RIGID BODY FIT / Target criteria: Cross-correlation coefficient
Output model

PDB-9cht:
Human E3 ligase E6AP in complex with HPV16-E6 and p53

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