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- EMDB-60925: Cryo-EM structure of CyclinD1 bound AMBRA1-DDB1 -

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Basic information

Entry
Database: EMDB / ID: EMD-60925
TitleCryo-EM structure of CyclinD1 bound AMBRA1-DDB1
Map data
Sample
  • Complex: Complex of AMBRA1-DDB1 bound to CyclinD1-CDK4
    • Protein or peptide: G1/S-specific cyclin-D1
    • Protein or peptide: Activating molecule in BECN1-regulated autophagy protein 1
    • Protein or peptide: DNA damage-binding protein 1
KeywordsE3 ligase / SIGNALING PROTEIN
Function / homology
Function and homology information


positive regulation of free ubiquitin chain polymerization / cyclin D1-CDK4 complex / cyclin D1-CDK6 complex / re-entry into mitotic cell cycle / Drug-mediated inhibition of CDK4/CDK6 activity / RUNX3 regulates WNT signaling / response to mitochondrial depolarisation / positive regulation of mitophagy / positive regulation of mammary gland epithelial cell proliferation / response to leptin ...positive regulation of free ubiquitin chain polymerization / cyclin D1-CDK4 complex / cyclin D1-CDK6 complex / re-entry into mitotic cell cycle / Drug-mediated inhibition of CDK4/CDK6 activity / RUNX3 regulates WNT signaling / response to mitochondrial depolarisation / positive regulation of mitophagy / positive regulation of mammary gland epithelial cell proliferation / response to leptin / Transcriptional regulation by RUNX2 / Leydig cell differentiation / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / Cul4-RING E3 ubiquitin ligase complex / cyclin-dependent protein serine/threonine kinase activator activity / UV-damage excision repair / proline-rich region binding / Regulation of RUNX1 Expression and Activity / response to iron ion / biological process involved in interaction with symbiont / neural tube development / positive regulation of regulatory T cell differentiation / cyclin-dependent protein serine/threonine kinase regulator activity / negative regulation of cardiac muscle cell apoptotic process / regulation of mitotic cell cycle phase transition / mammary gland epithelial cell proliferation / WD40-repeat domain binding / response to UV-A / Cul4A-RING E3 ubiquitin ligase complex / response to corticosterone / response to vitamin E / negative regulation of epithelial cell differentiation / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Macroautophagy / PTK6 Regulates Cell Cycle / negative regulation of reproductive process / negative regulation of developmental process / fat cell differentiation / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / microtubule organizing center / regulation of G1/S transition of mitotic cell cycle / response to magnesium ion / cullin family protein binding / viral release from host cell / protein phosphatase activator activity / Transcriptional Regulation by VENTX / RUNX3 regulates p14-ARF / axoneme / autophagosome assembly / mammary gland alveolus development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / response to X-ray / bicellular tight junction / ectopic germ cell programmed cell death / positive regulation of G1/S transition of mitotic cell cycle / ubiquitin-like ligase-substrate adaptor activity / positive regulation of viral genome replication / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / proteasomal protein catabolic process / endoplasmic reticulum unfolded protein response / cyclin-dependent protein kinase holoenzyme complex / mitophagy / lactation / phagocytic vesicle / mitotic G1 DNA damage checkpoint signaling / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of autophagy / positive regulation of gluconeogenesis / transcription repressor complex / autophagosome / cellular response to starvation / protein serine/threonine kinase activator activity / Ubiquitin-dependent degradation of Cyclin D / nucleotide-excision repair / liver regeneration / Recognition of DNA damage by PCNA-containing replication complex / G1/S transition of mitotic cell cycle / regulation of circadian rhythm / DNA Damage Recognition in GG-NER / Pre-NOTCH Transcription and Translation / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / SCF(Skp2)-mediated degradation of p27/p21 / RMTs methylate histone arginines / response to estrogen / Formation of Incision Complex in GG-NER / histone deacetylase binding / Wnt signaling pathway / response to calcium ion / neuron differentiation / Dual incision in TC-NER / protein polyubiquitination / Gap-filling DNA repair synthesis and ligation in TC-NER / positive regulation of protein catabolic process / Cyclin D associated events in G1 / cellular response to UV
Similarity search - Function
: / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal ...: / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / : / CPSF A subunit region / RSE1/DDB1/CPSF1 first beta-propeller / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / WD domain, G-beta repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
G1/S-specific cyclin-D1 / DNA damage-binding protein 1 / Activating molecule in BECN1-regulated autophagy protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.55 Å
AuthorsWang Y / Liu M / Su M-Y / Stjepanovic G
Funding support China, 1 items
OrganizationGrant numberCountry
Other government2024A1515011683 China
CitationJournal: Sci Adv / Year: 2025
Title: Mechanism of D-type cyclin recognition by the AMBRA1 E3 ligase receptor.
Authors: Yang Wang / Ming Liu / Shan Wang / Xinyi Mai / Xi Wang / Fei Teng / Tianrui Lyu / Ming-Yuan Su / Goran Stjepanovic /
Abstract: AMBRA1 is a tumor suppressor protein that functions as a substrate receptor in the ubiquitin conjugation system and regulates the stability of D-type cyclins and cell proliferation. Here, we present ...AMBRA1 is a tumor suppressor protein that functions as a substrate receptor in the ubiquitin conjugation system and regulates the stability of D-type cyclins and cell proliferation. Here, we present the cryo-EM structure of cyclin D1-bound AMBRA1-DDB1 complex at 3.55-Å resolution. The structure reveals a substrate interaction surface on the AMBRA1 WD40 domain that specifically binds to the C-terminal region of D-type cyclins. This interaction is dependent on the phosphorylation of Thr residue in the C-terminal phosphodegron site of D-type cyclins. The phosphodegron motif folds into a turn-like conformation, followed by a 3 helix that promotes its assembly with AMBRA1. In addition, we show that AMBRA1 mutants, which are defective in cyclin D1 binding, lead to cyclin D1 accumulation and DNA damage. Understanding the AMBRA1-D-type cyclin structure enhances the knowledge of the molecular mechanisms that govern the cell cycle control and may lead to potential therapeutic approaches for cancers linked to abnormal cyclin D activity.
History
DepositionJul 23, 2024-
Header (metadata) releaseApr 23, 2025-
Map releaseApr 23, 2025-
UpdateJul 16, 2025-
Current statusJul 16, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_60925.png

Downloads & links

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Map

FileDownload / File: emd_60925.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.192
Minimum - Maximum-0.4373974 - 0.99156445
Average (Standard dev.)0.000027097887 (±0.04336814)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 217.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_60925_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_60925_half_map_2.map
Projections & Slices
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Sample components

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Entire : Complex of AMBRA1-DDB1 bound to CyclinD1-CDK4

EntireName: Complex of AMBRA1-DDB1 bound to CyclinD1-CDK4
Components
  • Complex: Complex of AMBRA1-DDB1 bound to CyclinD1-CDK4
    • Protein or peptide: G1/S-specific cyclin-D1
    • Protein or peptide: Activating molecule in BECN1-regulated autophagy protein 1
    • Protein or peptide: DNA damage-binding protein 1

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Supramolecule #1: Complex of AMBRA1-DDB1 bound to CyclinD1-CDK4

SupramoleculeName: Complex of AMBRA1-DDB1 bound to CyclinD1-CDK4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 244 KDa

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Macromolecule #1: G1/S-specific cyclin-D1

MacromoleculeName: G1/S-specific cyclin-D1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.84709 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEHQLLCCEV ETIRRAYPDA NLLNDRVLRA MLKAEETCAP SVSYFKCVQK EVLPSMRKIV ATWMLEVCEE QKCEEEVFPL AMNYLDRFL SLEPVKKSRL QLLGATCMFV ASKMKETIPL TAEKLCIYTD NSIRPEELLQ MELLLVNKLK WNLAAMTPHD F IEHFLSKM ...String:
MEHQLLCCEV ETIRRAYPDA NLLNDRVLRA MLKAEETCAP SVSYFKCVQK EVLPSMRKIV ATWMLEVCEE QKCEEEVFPL AMNYLDRFL SLEPVKKSRL QLLGATCMFV ASKMKETIPL TAEKLCIYTD NSIRPEELLQ MELLLVNKLK WNLAAMTPHD F IEHFLSKM PEAEENKQII RKHAQTFVAL CATDVKFISN PPSMVAAGSV VAAVQGLNLR SPNNFLSYYR LTRFLSRVIK CD PDCLRAC QEQIEALLES SLRQAQQNMD PKAAEEEEEE EEEVDLAC(TPO)P TDVRDVDI

UniProtKB: G1/S-specific cyclin-D1

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Macromolecule #2: Activating molecule in BECN1-regulated autophagy protein 1

MacromoleculeName: Activating molecule in BECN1-regulated autophagy protein 1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.496871 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKVVPEKNAV RILWGRERGA RAMGAQRLLQ ELVEDKTRWM KWEGKRVELP DSPRSTFLLA FSPDRTLLAS THVNHNIYIT EVKTGKCVH SLIGHRRTPW CVTFHPTISG LIASGCLDGE VRIWDLHGGS ESWFTDSNNA IASLAFHPTA QLLLIATANE I HFWDWSRR ...String:
MKVVPEKNAV RILWGRERGA RAMGAQRLLQ ELVEDKTRWM KWEGKRVELP DSPRSTFLLA FSPDRTLLAS THVNHNIYIT EVKTGKCVH SLIGHRRTPW CVTFHPTISG LIASGCLDGE VRIWDLHGGS ESWFTDSNNA IASLAFHPTA QLLLIATANE I HFWDWSRR EPFAVVKTAS EMERVRLVRF DPLGHYLLTA IVNPSNSNIA NTTYRLQWWD FTKFDLPEIS NASVNVLVQN CK IYNDASC DISADGQLLA AFIPSSQRGF PDEGILAVYS LAPHNLGEML YTKRFGPNAI SVSLSPMGRY VMVGLASRRI LLH PSTEHM VAQVFRLQQA HGGETSMRRV FNVLYPMPAD QRRHVSINSA RWLPEPGLGL AYGTNKGDLV ICRPEALNSG

UniProtKB: Activating molecule in BECN1-regulated autophagy protein 1, Activating molecule in BECN1-regulated autophagy protein 1

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Macromolecule #3: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127.097469 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACIL EYKQSGESID IITRAHGNVQ DRIGRPSETG IIGIIDPECR MIGLRLYDGL FKVIPLDRDN KELKAFNIRL E ELHVIDVK ...String:
MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACIL EYKQSGESID IITRAHGNVQ DRIGRPSETG IIGIIDPECR MIGLRLYDGL FKVIPLDRDN KELKAFNIRL E ELHVIDVK FLYGCQAPTI CFVYQDPQGR HVKTYEVSLR EKEFNKGPWK QENVEAEASM VIAVPEPFGG AIIIGQESIT YH NGDKYLA IAPPIIKQST IVCHNRVDPN GSRYLLGDME GRLFMLLLEK EEQMDGTVTL KDLRVELLGE TSIAECLTYL DNG VVFVGS RLGDSQLVKL NVDSNEQGSY VVAMETFTNL GPIVDMCVVD LERQGQGQLV TCSGAFKEGS LRIIRNGIGI HEHA SIDLP GIKGLWPLRS DPNRETDDTL VLSFVGQTRV LMLNGEEVEE TELMGFVDDQ QTFFCGNVAH QQLIQITSAS VRLVS QEPK ALVSEWKEPQ AKNISVASCN SSQVVVAVGR ALYYLQIHPQ ELRQISHTEM EHEVACLDIT PLGDSNGLSP LCAIGL WTD ISARILKLPS FELLHKEMLG GEIIPRSILM TTFESSHYLL CALGDGALFY FGLNIETGLL SDRKKVTLGT QPTVLRT FR SLSTTNVFAC SDRPTVIYSS NHKLVFSNVN LKEVNYMCPL NSDGYPDSLA LANNSTLTIG TIDEIQKLHI RTVPLYES P RKICYQEVSQ CFGVLSSRIE VQDTSGGTTA LRPSASTQAL SSSVSSSKLF SSSTAPHETS FGEEVEVHNL LIIDQHTFE VLHAHQFLQN EYALSLVSCK LGKDPNTYFI VGTAMVYPEE AEPKQGRIVV FQYSDGKLQT VAEKEVKGAV YSMVEFNGKL LASINSTVR LYEWTTEKEL RTECNHYNNI MALYLKTKGD FILVGDLMRS VLLLAYKPME GNFEEIARDF NPNWMSAVEI L DDDNFLGA ENAFNLFVCQ KDSAATTDEE RQHLQEVGLF HLGEFVNVFC HGSLVMQNLG ETSTPTQGSV LFGTVNGMIG LV TSLSESW YNLLLDMQNR LNKVIKSVGK IEHSFWRSFH TERKTEPATG FIDGDLIESF LDISRPKMQE VVANLQYDDG SGM KREATA DDLIKVVEEL TRIH

UniProtKB: DNA damage-binding protein 1

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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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.198 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8wqr

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.55 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1015935
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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